15-33838071-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong
The NM_001036.6(RYR3):c.12091C>T(p.Arg4031Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,613,788 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 (★).
Frequency
Consequence
NM_001036.6 missense
Scores
Clinical Significance
Conservation
Publications
- genetic developmental and epileptic encephalopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
- congenital myopathyInheritance: AR Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152078Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000481 AC: 12AN: 249262 AF XY: 0.0000370 show subpopulations
GnomAD4 exome AF: 0.000120 AC: 176AN: 1461710Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 87AN XY: 727138 show subpopulations
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74288 show subpopulations
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
This sequence change replaces arginine with cysteine at codon 4031 of the RYR3 protein (p.Arg4031Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. In summary, this variant has uncertain impact on RYR3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a RYR3-related disease. This variant is present in population databases (rs376071087, ExAC 0.02%). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at