17-10531765-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_017534.6(MYH2):c.2565G>A(p.Met855Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M855K) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.2565G>A | p.Met855Ile | missense_variant | 22/40 | ENST00000245503.10 | |
MYHAS | NR_125367.1 | n.168-35772C>T | intron_variant, non_coding_transcript_variant | ||||
MYH2 | NM_001100112.2 | c.2565G>A | p.Met855Ile | missense_variant | 22/40 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH2 | ENST00000245503.10 | c.2565G>A | p.Met855Ile | missense_variant | 22/40 | 1 | NM_017534.6 | P1 | |
ENST00000399342.6 | n.207-1559C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251432Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135888
GnomAD4 exome AF: 0.000110 AC: 161AN: 1461884Hom.: 0 Cov.: 35 AF XY: 0.0000990 AC XY: 72AN XY: 727240
GnomAD4 genome AF: 0.000118 AC: 18AN: 152300Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 06, 2014 | - - |
Myopathy, proximal, and ophthalmoplegia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 855 of the MYH2 protein (p.Met855Ile). This variant is present in population databases (rs184494954, gnomAD 0.03%). 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: 195692). 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 | Sep 27, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 30, 2023 | The c.2565G>A (p.M855I) alteration is located in exon 22 (coding exon 20) of the MYH2 gene. This alteration results from a G to A substitution at nucleotide position 2565, causing the methionine (M) at amino acid position 855 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at