17-10521327-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_017534.6(MYH2):c.5779C>T(p.Arg1927Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,920 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
Consequence
NM_017534.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.5779C>T | p.Arg1927Trp | missense_variant | Exon 40 of 40 | ENST00000245503.10 | NP_060004.3 | |
MYH2 | NM_001100112.2 | c.5779C>T | p.Arg1927Trp | missense_variant | Exon 40 of 40 | NP_001093582.1 | ||
MYHAS | NR_125367.1 | n.168-46210G>A | intron_variant | Intron 2 of 10 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251446Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135890
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727218
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
Myopathy, proximal, and ophthalmoplegia Uncertain:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1927 of the MYH2 protein (p.Arg1927Trp). This variant is present in population databases (rs767382926, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MYH2-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 expected to disrupt MYH2 protein function with a positive 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