rs78165942
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000366574.7(RYR2):c.2397-6C>T 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 0.00248 in 1,596,156 control chromosomes in the GnomAD database, including 71 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 Benign (★★).
Frequency
Consequence
ENST00000366574.7 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.2397-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.2397-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001035.3 | ENSP00000355533 | P1 | |||
RYR2 | ENST00000659194.3 | c.2397-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENSP00000499653 | ||||||
RYR2 | ENST00000660292.2 | c.2397-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENSP00000499787 | ||||||
RYR2 | ENST00000609119.2 | c.2397-6C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes AF: 0.00990 AC: 1506AN: 152124Hom.: 28 Cov.: 32
GnomAD3 exomes AF: 0.00371 AC: 817AN: 220452Hom.: 13 AF XY: 0.00344 AC XY: 409AN XY: 119006
GnomAD4 exome AF: 0.00170 AC: 2455AN: 1443914Hom.: 43 Cov.: 31 AF XY: 0.00186 AC XY: 1333AN XY: 716550
GnomAD4 genome AF: 0.00990 AC: 1507AN: 152242Hom.: 28 Cov.: 32 AF XY: 0.00974 AC XY: 725AN XY: 74446
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2013 | 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. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2012 | 2397-6C>T in Intron 21 of RYR2: This variant is not expected to have clinical si gnificance because it is not located within the conserved +/- 1, 2 invariant reg ion. It has been identified in 3.8% (116/3076) of African American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; rs78165942). - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2023 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 02, 2016 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Arrhythmogenic right ventricular dysplasia 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at