rs749434532
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2
The NM_001035.3(RYR2):c.4990G>A(p.Val1664Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000356 in 1,461,694 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. V1664D) 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 -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4990G>A | p.Val1664Ile | missense_variant | Exon 37 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
RYR2 | ENST00000609119.2 | n.4990G>A | non_coding_transcript_exon_variant | Exon 37 of 104 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.4990G>A | p.Val1664Ile | missense_variant | Exon 37 of 106 | ENSP00000499787.2 | ||||
RYR2 | ENST00000659194.3 | c.4990G>A | p.Val1664Ile | missense_variant | Exon 37 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000402 AC: 10AN: 248998Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135116
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461694Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727128
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
This missense variant replaces valine with isoleucine at codon 1664 of the RYR2 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 cardiovascular disorders in the literature. This variant has been identified in 10/248998 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. -
Cardiomyopathy Uncertain:1
This missense variant replaces valine with isoleucine at codon 1664 of the RYR2 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 cardiovascular disorders in the literature. This variant has been identified in 10/248998 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
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009); This variant is associated with the following publications: (PMID: 19926015) -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at