rs868071612
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001035.3(RYR2):c.12235G>A(p.Asp4079Asn) 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. 14/21 in silico tools predict a benign 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. D4079Y) has been classified as Uncertain significance.
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.12235G>A | p.Asp4079Asn | missense_variant | 90/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.12235G>A | p.Asp4079Asn | missense_variant | 90/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.12256G>A | p.Asp4086Asn | missense_variant | 91/106 | ||||
RYR2 | ENST00000659194.3 | c.12223G>A | p.Asp4075Asn | missense_variant | 90/105 | ||||
RYR2 | ENST00000609119.2 | c.*3327G>A | 3_prime_UTR_variant, NMD_transcript_variant | 89/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 14, 2021 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with RYR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 4079 of the RYR2 protein (p.Asp4079Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at