rs1553529773
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001035.3(RYR2):c.6027T>G(p.Ile2009Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I2009I) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.6027T>G | p.Ile2009Met | missense_variant | 40/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.6027T>G | p.Ile2009Met | missense_variant | 40/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.6027T>G | p.Ile2009Met | missense_variant | 40/106 | ||||
RYR2 | ENST00000659194.3 | c.6027T>G | p.Ile2009Met | missense_variant | 40/105 | ||||
RYR2 | ENST00000609119.2 | c.6027T>G | p.Ile2009Met | missense_variant, NMD_transcript_variant | 40/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 13, 2016 | Variant summary: The RYR2 c.6027T>G (p.Ile2009Met) variant involves the alteration of a non- conserved nucleotide and 4/5 in silico tools predicting a benign outcome. The variant is absent from control dataset of ExAC (120306 chrs tested) and has not, to our knowledge, been reported in affected individuals via published reports or cited by a reputable database/clinical laboratory. Taking together, the variant was classified as VUS. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2017 | This variant does not occur within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a RYR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 2009 of the RYR2 protein (p.Ile2009Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at