1-237788065-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001035.3(RYR2):c.13406G>C(p.Arg4469Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000754 in 1,459,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R4469G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.13406G>C | p.Arg4469Thr | missense_variant | Exon 92 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.*4498G>C | non_coding_transcript_exon_variant | Exon 91 of 104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000609119.2 | n.*4498G>C | 3_prime_UTR_variant | Exon 91 of 104 | 5 | ENSP00000499659.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000122 AC: 3AN: 245632Hom.: 0 AF XY: 0.00000751 AC XY: 1AN XY: 133084
GnomAD4 exome AF: 0.00000754 AC: 11AN: 1459772Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6AN XY: 725924
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
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. 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 not expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 463565). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs759882217, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 4469 of the RYR2 protein (p.Arg4469Thr). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at