rs188671846
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):c.9450-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,606,270 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001035.3 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.9450-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.9450-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001035.3 | P1 | |||
RYR2 | ENST00000659194.3 | c.9450-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||||
RYR2 | ENST00000660292.2 | c.9450-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||||
RYR2 | ENST00000609119.2 | c.*485-3T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000473 AC: 72AN: 152184Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000395 AC: 94AN: 237708Hom.: 0 AF XY: 0.000351 AC XY: 45AN XY: 128388
GnomAD4 exome AF: 0.000281 AC: 408AN: 1453968Hom.: 0 Cov.: 30 AF XY: 0.000269 AC XY: 194AN XY: 722316
GnomAD4 genome ? AF: 0.000473 AC: 72AN: 152302Hom.: 1 Cov.: 32 AF XY: 0.000577 AC XY: 43AN XY: 74468
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 24, 2012 | The 9450-3T>C variant in RYR2 has not been reported in the literature but has be en previously identified in one Caucasian individual with DCM by our laboratory. This variant has been identified in 1/28 Iberian chromosomes from a broad popul ation by the 1000 Genomes project (dbSNP rs188671846), though this may be a pres ymptomatic individual. In addition, this variant is located in the 3' splice reg ion but computational tools do not suggest an impact to splicing. Additional inf ormation is needed to fully assess the clinical significance of this variant. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2024 | Variant summary: RYR2 c.9450-3T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 0.0003 in 1606270 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, c.9450-3T>C has not been reported in the literature in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28404607). ClinVar contains an entry for this variant (Variation ID: 43838). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2015 | 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. - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 25, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at