rs765797952
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_002471.4(MYH6):c.3575C>T(p.Ala1192Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000877 in 1,597,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1192A) has been classified as Likely benign.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3575C>T | p.Ala1192Val | missense_variant | 26/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3575C>T | p.Ala1192Val | missense_variant | 26/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151772Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000433 AC: 1AN: 230956Hom.: 0 AF XY: 0.00000791 AC XY: 1AN XY: 126378
GnomAD4 exome AF: 0.00000830 AC: 12AN: 1445308Hom.: 0 Cov.: 34 AF XY: 0.00000836 AC XY: 6AN XY: 717766
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151772Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74110
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1192 of the MYH6 protein (p.Ala1192Val). This variant is present in population databases (rs765797952, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 239168). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 09, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2023 | The p.A1192V variant (also known as c.3575C>T), located in coding exon 24 of the MYH6 gene, results from a C to T substitution at nucleotide position 3575. The alanine at codon 1192 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at