14-23390401-C-A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002471.4(MYH6):c.3388G>T(p.Ala1130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130T) has been classified as Benign.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathy 14Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
- Keppen-Lubinsky syndromeInheritance: AD Classification: MODERATE Submitted by: Illumina
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- atrial septal defect 3Inheritance: AD Classification: LIMITED Submitted by: G2P
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3388G>T | p.Ala1130Ser | missense_variant | Exon 26 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD2 exomes AF: 0.00000410 AC: 1AN: 243682 AF XY: 0.00000754 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4AN: 1457832Hom.: 0 Cov.: 37 AF XY: 0.00000276 AC XY: 2AN XY: 725158 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1130 of the MYH6 protein (p.Ala1130Ser). This variant is present in population databases (rs28730771, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at