rs138206136
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The ENST00000245503.10(MYH2):c.2823G>T(p.Glu941Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000736 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. E941K) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000245503.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.2823G>T | p.Glu941Asp | missense_variant | 23/40 | ENST00000245503.10 | NP_060004.3 | |
MYHAS | NR_125367.1 | n.168-37588C>A | intron_variant, non_coding_transcript_variant | |||||
MYH2 | NM_001100112.2 | c.2823G>T | p.Glu941Asp | missense_variant | 23/40 | NP_001093582.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH2 | ENST00000245503.10 | c.2823G>T | p.Glu941Asp | missense_variant | 23/40 | 1 | NM_017534.6 | ENSP00000245503 | P1 | |
ENST00000399342.6 | n.207-3375C>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000442 AC: 111AN: 251214Hom.: 0 AF XY: 0.000479 AC XY: 65AN XY: 135792
GnomAD4 exome AF: 0.000761 AC: 1112AN: 1461530Hom.: 0 Cov.: 34 AF XY: 0.000758 AC XY: 551AN XY: 727036
GnomAD4 genome AF: 0.000493 AC: 75AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74414
ClinVar
Submissions by phenotype
Myopathy, proximal, and ophthalmoplegia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 941 of the MYH2 protein (p.Glu941Asp). This variant is present in population databases (rs138206136, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. 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: 465931). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 01, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at