14-23385954-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_002471.4(MYH6):c.5137G>A(p.Glu1713Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,076 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 (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
MYH6
NM_002471.4 missense
NM_002471.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.78
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5137G>A | p.Glu1713Lys | missense_variant | 34/39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.5137G>A | p.Glu1713Lys | missense_variant | 34/39 | 5 | NM_002471.4 | ENSP00000386041.3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250104Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135276
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727242
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152192Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1713 of the MYH6 protein (p.Glu1713Lys). This variant is present in population databases (rs369275573, gnomAD 0.02%). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 32183154). ClinVar contains an entry for this variant (Variation ID: 263451). 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 with a negative predictive value of 80%. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35621855, 32183154, 33309763) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2023 | The p.E1713K variant (also known as c.5137G>A), located in coding exon 32 of the MYH6 gene, results from a G to A substitution at nucleotide position 5137. The glutamic acid at codon 1713 is replaced by lysine, an amino acid with similar properties. This variant has been detected in an individual from a left ventricular non-compaction cohort (Hirono K et al. J Clin Med, 2020 Mar;9). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at