rs769341738
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_002471.4(MYH6):c.2354G>A(p.Arg785His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,948 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. R785C) has been classified as Likely benign.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.2354G>A | p.Arg785His | missense_variant | 20/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.2354G>A | p.Arg785His | missense_variant | 20/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251142Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135768
GnomAD4 exome AF: 0.0000705 AC: 103AN: 1461704Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727168
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74372
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 785 of the MYH6 protein (p.Arg785His). This variant is present in population databases (rs769341738, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 407156). 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 MYH6 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2022 | The p.R785H variant (also known as c.2354G>A), located in coding exon 18 of the MYH6 gene, results from a G to A substitution at nucleotide position 2354. The arginine at codon 785 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at