{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/ff9e7a2b-a9b2-4b24-9710-692ab7a1823e/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1812056141", "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0015152", "id": "MONDO:0015152", "label": "autosomal recessive limb-girdle muscular dystrophy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1765", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1766", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1765/1767", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "curated variant:\ndelta 0.63 for acceptor loss (ref 0.97, alt 0.34)\ndelta 0.68 for donor loss (ref 0.88, alt 0.19)\nNIF impact: -87%, -82%, -38%\n\ncomparison variants:\nc.1782+2T>C\nreported in PMID: 31268554\ndelta 0.64 for acceptor loss (ref 0.97, alt 0.32) - comparable\ndelta 0.88 for donor loss (ref 0.88, alt 0) - slightly higher\nNIF impact -100%, -99%, -90% \nGENEie considers this variant to have a different impact\n\nc.1782+1G>A\nreported in PMID: 39103709, 35169782\ndelta 0.63 for acceptor loss (ref 0.97, alt 0.34) - same\ndelta 0.88 for donor loss (ref 0.88, alt 0) - slightly higher\n\nc.1782+1G>T\nreported in PMID: 31268554\ndelta 0.7 for acceptor loss (ref 0.97, alt 0.27) - comparable\ndelta 0.88 for donor loss (ref 0.88, alt 0) - slightly higher\n\nPS1_Moderate if a comparison variant considered to have same predicted effect with equivalent prediction strength and classified at P, PS1_Supporting if LP\n1 or 2 Bayesian pts would not be sufficient to upgrade the classification (currently at 7)\ncuration of comparison variants not pursued at this time", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1765/1767", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1766", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1765", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1762", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1763", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1762/1764", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The NM_000070.3: c.1782G>A variant in CAPN3 is a synonymous variant that is not expected to influence the protein amino acid sequence, p.(Val594=) but affects the last nucleotide of exon 14. SpliceAI gives a delta score of 0.68 for loss of the canonical splice donor site for exon 14 and 0.63 for loss of the canonical acceptor, suggesting it may affect splicing. RNAseq analysis on RNA from blood from a carrier of this variant has demonstrated that it causes near-complete missplicing, including skipping of exons 14 and 15 as well as of exons 14-16. Both of these exon skipping events are expected to introduce a frameshift and premature truncation with nonsense mediated decay expected (ClinVar SCV006324308.1 internal data communication; PVS1_RNA_Strong). In skeletal muscle, it may be associated with skipping of exon 14 only, which would also be expected to introduce a frameshift, premature truncation, and nonsense-mediated decay.\n\nSCV006324308.1: \"RNA studies showed near complete mis-splicing, including exon 14-15 skipping and exon 14-15-16 skipping of the CAPN3 transcript\".\nthrough a request for additional data, the RNAseq analysis report from RNA4RD was provided (from Sandra Cooper), estimating 94% loss of canonical splicing \n\nskipping of exon 14 is out of frame\nskipping of exons 14-15 is out of frame\nskipping of exons 14-16 is out of frame", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1762/1764", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1763", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1762", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1610", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "This variant has been observed in a heterozygous state in at least two individuals with progressive limb girdle muscle weakness, including in unconfirmed phase with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts, GRASP-LGMD Consortium internal data communication) and confirmed in trans with a VUS (0.25 pts, ClinVar SCV006324308.1 internal data communication) (PM3_Supporting\n\nthis variant is not in gnomAD v2 and so co-occurrence cannot be assessed", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1609", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1654", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1655", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1654/1656", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "Synonymous variant located in a splice region and predicted/experimentally shown to affect splicing.", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1654/1656", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1655", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1654", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The NM_000070.3: c.1782G>A variant in CAPN3 is a synonymous variant that is not expected to influence the protein amino acid sequence, p.(Val594=). It affects the last nucleotide of exon 14 and is predicted to affect splicing with a SpliceAI delta score of 0.68 for loss of the canonical splice donor site for exon 14 and 0.63 for loss of the canonical acceptor. Skipping of exon 14, which is out of frame, would be expected to introduce a frameshift.\n\nDo not apply if PVS1_RNA applied at any strength.\n\nSplice AI \ndelta 0.68 for donor loss (ref 0.88, alt 0.19)\ndelta 0.63 for acceptor loss (ref 0.97, alt 0.34)\nskipping of exon 14, which is out of frame, seems like most likely outcome\n\nGENEie\n75% probability splice altering\nNIF impact:\nU5 -87%\nU1 -82%\nU6 -38%\nexon 14 skipping observed in 62 samples in SpliceVault\n", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "This variant has been observed with a second presumed diagnostic CAPN3 variant in at least one individual who displayed progressive limb girdle muscle weakness (GRASP-LGMD Consortium internal data communication; ClinVar SCV006324308.1) (PP4). ", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA489885243/MONDO:0015152/187/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179864 European (non-Finnish) alleles, which is less than the VCEP threshold (0.0001), meeting the criterion for PM2_Supporting.", "contributionDate": { "date": "2026/5/7", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA489885243/MONDO:0015152/187/ci/CA489885243/MONDO:0015152/187.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA489885243/MONDO:0015152/187", "metadata": { "created": "2026-05-07T14:39:26.104Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Thu, 07 May 2026 14:39:25 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "ff9e7a2b-a9b2-4b24-9710-692ab7a1823e", "variant": { "@id": "https://reg.genome.network/allele/CA489885243", "id": "CAR:CA489885243", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000070.3:c.1782G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000070.3(CAPN3):c.1782G>A (p.Val594=)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T00:18:28.180Z" } }, "status": { "code": 200, "name": "OK" } }