rs776971183
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_002471.4(MYH6):c.2554G>A(p.Ala852Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,120 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. A852A) 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.2554G>A | p.Ala852Thr | missense_variant | 21/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.2554G>A | p.Ala852Thr | missense_variant | 21/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727248
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74380
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2022 | This variant is present in population databases (rs776971183, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 852 of the MYH6 protein (p.Ala852Thr). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). 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: 263991). - |
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 | Jan 10, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 29, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2022 | The p.A852T variant (also known as c.2554G>A), located in coding exon 19 of the MYH6 gene, results from a G to A substitution at nucleotide position 2554. The alanine at codon 852 is replaced by threonine, an amino acid with similar properties. This variant has been detected in a sudden death cohort (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). 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