Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001164508.2(NEB):c.25463A>G (p.Lys8488Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA1905697

435961 (ClinVar)

Gene: NEB

Condition: nemaline myopathy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 59f4fd4f-d4e3-4450-a4c7-d41375b53414

Approved on: 2024-08-07

Published on: 2024-10-01

HGVS expressions

NM_001164508.2:c.25463A>G

NM_001164508.2(NEB):c.25463A>G (p.Lys8488Arg)

NC_000002.12:g.151485875T>C

CM000664.2:g.151485875T>C

NC_000002.11:g.152342389T>C

CM000664.1:g.152342389T>C

NC_000002.10:g.152050635T>C

NG_009382.2:g.253613A>G

ENST00000434685.6:c.3772A>G

ENST00000688578.1:c.2062A>G

ENST00000689642.1:n.1282A>G

ENST00000690043.1:c.7168A>G

ENST00000693000.1:n.3354A>G

ENST00000397345.8:c.25463A>G

ENST00000427231.7:c.25463A>G

ENST00000172853.14:c.19895A>G

ENST00000397337.6:c.1864A>G

ENST00000397345.7:c.25463A>G

ENST00000409198.5:c.19895A>G

ENST00000413693.5:c.8909A>G

ENST00000427231.6:c.25463A>G

ENST00000434685.5:c.2185A>G

ENST00000454583.6:c.2655+2540T>C

ENST00000603639.5:c.25463A>G

ENST00000604864.5:c.25463A>G

ENST00000618972.4:c.25568A>G

NM_001164507.1:c.25463A>G

NM_001164508.1:c.25463A>G

NM_001271208.1:c.25568A>G

NM_004543.4:c.19895A>G

NM_001271208.2:c.25568A>G

NM_004543.5:c.19895A>G

NM_001164507.2:c.25463A>G

Likely Benign

BS1

BA1 PP3 PM3 PM2 BP4

Evidence Links 0

Expert Panel

Congenital Myopathies VCEP

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 c.25463A>G (p.Lys8488Arg) variant in NEB is a missense variant predicted to cause substitution of lysine by arginine at amino acid 8488. The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0009555 (1161/1179882 alleles) in the European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold (MAF≥0.000237) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.174, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BS1. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)

BS1

The highest population minor allele frequency in gnomAD v4.1.0 is 0.0009840 (1161/1179882 alleles, filtering AF: 0.0009555) in the European (non-Finnish) population, which is higher than the ClinGen Congenital Myopathies threshold (MAF ≥ 0.000237) for BS1, and therefore meets this criterion

BA1

PP3

The computational predictor REVEL gives a score of 0.174, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function

PM3

Identified in 3 unrelated individuals without a second NEB variant by GeneDx (SCV000975633.3): a patient with syncope, arthralgia, weakness, and fatigue, 2nd patient with arthrogryposis and congenital skeletal dysplasia, and 3rd patient with muscle fatigue and weakness

PM2

BP4

The computational predictor REVEL gives a score of 0.174, which is neither above nor below the thresholds predicting a damaging or benign impact on NEB function

Curation History

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