rs147606900
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_002471.4(MYH6):c.1252G>A(p.Val418Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.1252G>A | p.Val418Met | missense_variant | Exon 13 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000231 AC: 58AN: 251484Hom.: 0 AF XY: 0.000213 AC XY: 29AN XY: 135920
GnomAD4 exome AF: 0.0000910 AC: 133AN: 1461892Hom.: 1 Cov.: 32 AF XY: 0.0000976 AC XY: 71AN XY: 727246
GnomAD4 genome AF: 0.000138 AC: 21AN: 152350Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74508
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
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not specified Uncertain:1Benign:1
The Val418Met variant in MYH6 has been identified in 1/8600 European American an d 1/4406 African American chromosomes from broad populations by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS; dbSNP rs72646819). These c ould represent presymptomatic individuals. Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provi de strong support for or against an impact to the protein. Additional informatio n is needed to fully assess the clinical significance of this variant. -
Variant summary: MYH6 c.1252G>A (p.Val418Met) results in a conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251484 control chromosomes, predominantly at a frequency of 0.002 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1252G>A has been reported in the literature in individuals affected with DCM and HCM (Pugh_2014, Mademont-Soler_2017, Tran_2019). These reports also suggest that this variant is unlikely to associate with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Benign:2
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Hypertrophic cardiomyopathy 14 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at