rs928224285
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001035.3(RYR2):c.12215C>T(p.Thr4072Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,266 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. T4072P) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.12215C>T | p.Thr4072Met | missense_variant | 90/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.12215C>T | p.Thr4072Met | missense_variant | 90/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.12236C>T | p.Thr4079Met | missense_variant | 91/106 | ||||
RYR2 | ENST00000659194.3 | c.12203C>T | p.Thr4068Met | missense_variant | 90/105 | ||||
RYR2 | ENST00000609119.2 | c.*3307C>T | 3_prime_UTR_variant, NMD_transcript_variant | 89/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000324 AC: 8AN: 247018Hom.: 0 AF XY: 0.0000298 AC XY: 4AN XY: 134164
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461116Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6AN XY: 726802
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/275082 chromosomes (9/34300 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2023 | This missense variant replaces threonine with methionine at codon 4072 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 RYR2-related disorders in the literature. This variant has been identified in 10/278420 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; 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) - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at