chr14-23386608-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_002471.4(MYH6):c.4666G>A(p.Glu1556Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,464,722 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. E1556E) has been classified as 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.4666G>A | p.Glu1556Lys | missense_variant | 33/39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.4666G>A | p.Glu1556Lys | missense_variant | 33/39 | 5 | NM_002471.4 | ENSP00000386041 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000608 AC: 9AN: 148104Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000842 AC: 21AN: 249316Hom.: 0 AF XY: 0.0000891 AC XY: 12AN XY: 134678
GnomAD4 exome AF: 0.0000311 AC: 41AN: 1316618Hom.: 0 Cov.: 61 AF XY: 0.0000245 AC XY: 16AN XY: 652200
GnomAD4 genome AF: 0.0000608 AC: 9AN: 148104Hom.: 0 Cov.: 31 AF XY: 0.0000691 AC XY: 5AN XY: 72322
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 17, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 537962). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. This variant is present in population databases (rs148582147, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1556 of the MYH6 protein (p.Glu1556Lys). - |
Atrial septal defect 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 11, 2018 | ACMG codes: PP3, PP4 - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2023 | The p.E1556K variant (also known as c.4666G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4666. The glutamic acid at codon 1556 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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