rs187977513
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):c.8831-9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,584,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001035.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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RYR2 | ENST00000366574.7 | c.8831-9A>C | intron_variant | Intron 60 of 104 | 1 | NM_001035.3 | ENSP00000355533.2 | |||
RYR2 | ENST00000609119.2 | n.8831-2417A>C | intron_variant | Intron 60 of 103 | 5 | ENSP00000499659.2 | ||||
RYR2 | ENST00000660292.2 | c.8831-9A>C | intron_variant | Intron 60 of 105 | ENSP00000499787.2 | |||||
RYR2 | ENST00000659194.3 | c.8831-9A>C | intron_variant | Intron 60 of 104 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000235 AC: 57AN: 242464Hom.: 0 AF XY: 0.000274 AC XY: 36AN XY: 131228
GnomAD4 exome AF: 0.000301 AC: 431AN: 1432012Hom.: 1 Cov.: 25 AF XY: 0.000314 AC XY: 224AN XY: 713386
GnomAD4 genome AF: 0.000263 AC: 40AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74476
ClinVar
Submissions by phenotype
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Variant summary: RYR2 c.8831-9A>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 242464 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.8831-9A>C in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign while two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
not provided Uncertain:1Benign:1
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Sinus bradycardia;C0340279:Ventricular hypertrophy;C1560305:Prolonged QTc interval;C4021133:Left ventricular noncompaction cardiomyopathy;C4022814:Abnormal trabecular meshwork morphology;CN130023:Heart, malformation of Uncertain:1
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Catecholaminergic polymorphic ventricular tachycardia Benign:1
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Cardiomyopathy Benign:1
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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