Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001164508.2(NEB):c.19944G>A (p.Ser6648=)

CA1907493

235402 (ClinVar)

Gene: NEB
Condition: nemaline myopathy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 78612d0a-b94c-43f5-94f6-40cb61b477a3
Approved on: 2025-05-12
Published on: 2025-06-24

HGVS expressions

NM_001164508.2:c.19944G>A
NM_001164508.2(NEB):c.19944G>A (p.Ser6648=)
NC_000002.12:g.151551738C>T
CM000664.2:g.151551738C>T
NC_000002.11:g.152408252C>T
CM000664.1:g.152408252C>T
NC_000002.10:g.152116498C>T
NG_009382.2:g.187750G>A
ENST00000434685.6:c.26+3193G>A
ENST00000690043.1:c.2795G>A
ENST00000397345.8:c.19944G>A
ENST00000427231.7:c.19944G>A
ENST00000172853.14:c.14841G>A
ENST00000397345.7:c.19944G>A
ENST00000409198.5:c.14841G>A
ENST00000413693.5:c.4134G>A
ENST00000427231.6:c.19944G>A
ENST00000603639.5:c.19944G>A
ENST00000604864.5:c.19944G>A
ENST00000618972.4:c.19944G>A
NM_001164507.1:c.19944G>A
NM_001164508.1:c.19944G>A
NM_001271208.1:c.19944G>A
NM_004543.4:c.14841G>A
NM_001271208.2:c.19944G>A
NM_004543.5:c.14841G>A
NM_001164507.2:c.19944G>A
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Pathogenic

Met criteria codes 5
PS3 PP3 PP4 PP1 PM3_Strong
Not Met criteria codes 21
BP7 BP5 BP3 BP4 BP1 BP2 PS1 PS2 PS4 BA1 PP2 PM6 PM2 PM5 PM1 PM4 BS3 BS4 BS1 PVS1 BS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NEB Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The NM_001164508.2(NEB):c.19944G>A (p.Ser6648=) variant in NEB is a synonymous variant located at the intron exon boundary of exon 129. mRNA characterization of homozygous probands displayed that the variant abolishes the normal donor splice site, shifting towards the use of an alternative (cryptic) splice site in intron 129 which causes a partial intronic retention of 120bp that creates a premature stop codon and shorter polypeptide (PS3) (PMID: 26841830, PMID: 25205138). The computational splicing predictor SpliceAI gives a score of 0.77 for donor loss, predicting splice site disruption (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001659 (1/6026) alleles) in an unspecified ethnic group (no population codes met). This variant has been identified in at least 9 probands in either a homozygous state or with a second likely pathogenic, pathogenic, or rare uncertain variant (PM3_Strong) (PMID 26841830, 36233295, 25205138, 36233295, 37460656, 32222963, 36714460). At least one proband homozygous for the variant had an affected sibling also homozygous for the variant (PP1) (PMID: 37460656). Nemaline rods have been observed in at least one proband identified with the variant (PP4) (PMID: 26841830). In summary, this variant meets the criteria to be classified as pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PS3, PM3_Strong, PP4, PP3, PP1); ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 5/12/2025)
Met criteria codes
PS3
Variant is located at the intron exon boundary of exon 129 in NEB, in which loss of function is a known mechanism of disease. PMID: 26841830 discusses in P3 who is homozygous for the variant had characterization of the mRNA level where the mutation abolishes the normal donor splice site, shifting towards the use of an alternative (cryptic) splice site in intron 129 which originates a premature stop codon and shorter polypeptide. The variant was also described in two families in PMID: 25205138. The outcome of the splice site change is a partial intronic retention 120bp creating a premature termination codon and a shortened nebulin protein.
PP3
SpliceAI is >0.5 (0.77 for donor loss) which is above the threshold for calling PP3
PP4
PMID: 26841830 describes P3, the patient homozygous for the variant, as having rods seen in their muscle biopsy
PP1
PMID: 37460656 reported the variant in an assumed homozygous state in 2 siblings. Their father was heterozygous and their mother was not tested
PM3_Strong
Variant currently scores 2.5 points on the PM3 chart. This variant has been identified in at least 9 probands in either a homozygous state or with a second likely pathogenic, pathogenic, or rare uncertain variant (PM3_Strong) (PMID 26841830, 36233295, 25205138, 36233295, 37460656, 32222963, 36714460).
Not Met criteria codes
BP7
Splicing appears affected
BP5
No alternate molecular basis for disease
BP3
Synonymoys variant
BP4
Computational evidence suggests a deleterious effect on gene or gene product.
BP1
Synonymous variant
BP2
Autosomal recessive condition without other pathogenic variants in trans
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
Recessive condition, variants appear to be inherited
PS4
No case control studies identified.
BA1
PM2 met; Allele frequency is 0.00002820 in gnomAD, which is below the NEB threshold of 0.0000559 to invoke PM2
PP2
Synonymous variant
PM6
Recessive condition, variants appear to be inherited
PM2
The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001659 (1/6026) alleles) in an unspecified ethnic group, which is above the ClinGen Congenital Myopathies VCEP threshold (≤0.0000559) for PM2_Supporting, but lower than the ClinGen Congenital Myopathies VCEP threshold (≥0.000237) for BS1 therefore population criteria cannot be invoked.
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No defined hot spots for NEB
PM4
Synonymous variant
BS3
Functional studies support a damaging effect
BS4
Variant appears to segregate in affected individuals
BS1
PM2 met; Allele frequency is 0.00002820 in gnomAD, which is below the NEB threshold of 0.0000559 to invoke PM2
PVS1
Functional data supporting criteria used instead of PVS1
BS2
No homozygotes in gnomAD
Curation History
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