rs779358618
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000540.3(RYR1):c.15061G>T(p.Asp5021Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,862 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D5021D) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.15061G>T | p.Asp5021Tyr | missense_variant | 106/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.15061G>T | p.Asp5021Tyr | missense_variant | 106/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251464Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135910
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727234
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 5021 of the RYR1 protein (p.Asp5021Tyr). This variant is present in population databases (rs779358618, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 590480). 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 RYR1 protein function with a positive predictive value of 95%. 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 | PreventionGenetics, part of Exact Sciences | Jan 22, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at