chr17-10526786-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_017534.6(MYH2):c.4000G>T(p.Ala1334Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1334T) has been classified as Uncertain significance.
Frequency
Consequence
NM_017534.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.4000G>T | p.Ala1334Ser | missense_variant | Exon 30 of 40 | ENST00000245503.10 | NP_060004.3 | |
MYH2 | NM_001100112.2 | c.4000G>T | p.Ala1334Ser | missense_variant | Exon 30 of 40 | NP_001093582.1 | ||
MYHAS | NR_125367.1 | n.168-40751C>A | intron_variant | Intron 2 of 10 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251330Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135854
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Myopathy, proximal, and ophthalmoplegia Uncertain:2
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1334 of the MYH2 protein (p.Ala1334Ser). This variant is present in population databases (rs779257410, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 465938). 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 MYH2 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at