rs202226983
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate
The NM_000540.3(RYR1):c.13849G>A(p.Gly4617Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000818 in 1,613,534 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4617E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 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 |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.13849G>A | p.Gly4617Arg | missense_variant | 95/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.13849G>A | p.Gly4617Arg | missense_variant | 95/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000924 AC: 14AN: 151554Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251442Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135892
GnomAD4 exome AF: 0.0000807 AC: 118AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46AN XY: 727236
GnomAD4 genome ? AF: 0.0000923 AC: 14AN: 151670Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6AN XY: 74150
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 03, 2024 | This missense variant replaces glycine with arginine at codon 4617 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 39/282790 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2023 | This missense variant replaces glycine with arginine at codon 4617 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 39/282790 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 27, 2021 | - - |
RYR1-Related Disorders Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at