rs776093828
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_000540.3(RYR1):c.5650G>A(p.Gly1884Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,455,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.5650G>A | p.Gly1884Ser | missense_variant | Exon 35 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.5650G>A | p.Gly1884Ser | missense_variant | Exon 35 of 105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000599547.6 | n.5650G>A | non_coding_transcript_exon_variant | Exon 35 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1455818Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 724604
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
RYR1-related disorder Uncertain:1
This sequence change replaces glycine with serine at codon 1884 of the RYR1 protein (p.Gly1884Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Malignant hyperthermia, susceptibility to, 1 Uncertain:1
This missense variant replaces glycine with serine at codon 1884 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 not been identified 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at