rs863225269
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002471.4(MYH6):c.3193dupC(p.Gln1065fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MYH6
NM_002471.4 frameshift
NM_002471.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.65
Genes affected
MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-23392969-T-TG is Pathogenic according to our data. Variant chr14-23392969-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 217832.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3193dupC | p.Gln1065fs | frameshift_variant | 24/39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3193dupC | p.Gln1065fs | frameshift_variant | 24/39 | 5 | NM_002471.4 | ENSP00000386041.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Apr 21, 2015 | This MYBPC3 Lys1065fs variant results from a single bp insertion, which is predicted to cause a frameshift at codon 1065 and premature stop codon 12 amino acids downstream. This alteration is predicted to lead to a truncated or absent protein. This variant is absent from population datasets including the 1000 genomes project (http://www.1000genomes.org/) and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). MYBPC3 Lys1065fs has been identified in multiple unrelated HCM cases (see references). We have identified the this variant in one male HCM patient. Familial segregation revealed his affected nephew to also carried this variant. Based on the absence of this variant in the general population, observations of the variant in multiple unrelated HCM patients reported in the literature, and that loss-of-function variants in MYBPC3 are an established mechanism of disease in HCM, we classify MYBPC3 Lys1065fs as "pathogenic". - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at