chr17-10527799-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_017534.6(MYH2):c.3820C>T(p.Arg1274Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,613,992 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1274Q) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH2 | NM_017534.6 | c.3820C>T | p.Arg1274Trp | missense_variant | 28/40 | ENST00000245503.10 | |
MYHAS | NR_125367.1 | n.168-39738G>A | intron_variant, non_coding_transcript_variant | ||||
MYH2 | NM_001100112.2 | c.3820C>T | p.Arg1274Trp | missense_variant | 28/40 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH2 | ENST00000245503.10 | c.3820C>T | p.Arg1274Trp | missense_variant | 28/40 | 1 | NM_017534.6 | P1 | |
ENST00000399342.6 | n.207-5525G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152110Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251316Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135830
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727184
GnomAD4 genome AF: 0.000276 AC: 42AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74428
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2022 | The c.3820C>T (p.R1274W) alteration is located in exon 28 (coding exon 26) of the MYH2 gene. This alteration results from a C to T substitution at nucleotide position 3820, causing the arginine (R) at amino acid position 1274 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Myopathy, proximal, and ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1274 of the MYH2 protein (p.Arg1274Trp). This variant is present in population databases (rs191102801, gnomAD 0.07%). 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: 534342). 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 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32579932, 28719003, 26740555) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at