NM_001130987.2:c.605C>A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.509C>A variant in DYSF, which is also known as NM_001130987.2: c.605C>A p.(Ala202Glu), is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 170 (p.Ala170Glu). The filtering allele frequency of the variant is 0.01467 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 2546/251252), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been identified in individuals with LGMD (e.g., PMID:16010686, 25135358), its frequency in control populations is high relative to disease prevalence, and additional potentially causative variants were either identified as well or their presence not comprehensively ruled out (PM3 not met). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.22, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147766/MONDO:0015152/180
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.605C>A | p.Ala202Glu | missense_variant | Exon 7 of 56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.509C>A | p.Ala170Glu | missense_variant | Exon 6 of 55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.00967 AC: 1472AN: 152168Hom.: 9 Cov.: 32
GnomAD3 exomes AF: 0.0101 AC: 2546AN: 251252Hom.: 16 AF XY: 0.0102 AC XY: 1380AN XY: 135816
GnomAD4 exome AF: 0.0124 AC: 18138AN: 1461844Hom.: 134 Cov.: 32 AF XY: 0.0121 AC XY: 8810AN XY: 727216
GnomAD4 genome AF: 0.00966 AC: 1471AN: 152286Hom.: 9 Cov.: 32 AF XY: 0.00901 AC XY: 671AN XY: 74464
ClinVar
Submissions by phenotype
not specified Benign:6
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p.Ala202Glu in exon 7 of DYSF: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (132/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34999029). -
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Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided Benign:4
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DYSF: BP4, BS1, BS2 -
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Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Autosomal recessive limb-girdle muscular dystrophy Benign:1
The NM_003494.4: c.509C>A variant in DYSF, which is also known as NM_001130987.2: c.605C>A p.(Ala202Glu), is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 170 (p.Ala170Glu). The filtering allele frequency of the variant is 0.01467 for European (non-Finnish) exome chromosomes in gnomAD v2.1.1 (the lower threshold of the 95% CI of 2546/251252), which is higher than the VCEP threshold of 0.003 (BA1). While this variant has been identified in individuals with LGMD (e.g., PMID: 16010686, 25135358), its frequency in control populations is high relative to disease prevalence, and additional potentially causative variants were either identified as well or their presence not comprehensively ruled out (PM3 not met). The SpliceAI score for this variant is 0, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.22, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. -
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
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Miyoshi muscular dystrophy 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at