rs780970109
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001036.6(RYR3):c.962G>A(p.Arg321Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,460,420 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321W) has been classified as Uncertain significance.
Frequency
Consequence
NM_001036.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.962G>A | p.Arg321Gln | missense_variant | 10/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.962G>A | p.Arg321Gln | missense_variant | 10/104 | 1 | NM_001036.6 | P4 | |
RYR3 | ENST00000389232.9 | c.962G>A | p.Arg321Gln | missense_variant | 10/104 | 5 | A1 | ||
RYR3 | ENST00000415757.7 | c.962G>A | p.Arg321Gln | missense_variant | 10/103 | 2 | A2 | ||
RYR3 | ENST00000634418.1 | c.962G>A | p.Arg321Gln | missense_variant | 10/102 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000813 AC: 2AN: 245884Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133260
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1460420Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 726310
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 23, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 321 of the RYR3 protein (p.Arg321Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 579964). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at