1-237711741-T-C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001035.3(RYR2):c.10231-4T>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 0.000267 in 1,538,886 control chromosomes in the GnomAD database, including 6 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.10231-4T>C | 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.10231-4T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001035.3 | ENSP00000355533 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000604 AC: 92AN: 152200Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.000726 AC: 165AN: 227240Hom.: 0 AF XY: 0.000620 AC XY: 76AN XY: 122570
GnomAD4 exome AF: 0.000230 AC: 319AN: 1386568Hom.: 2 Cov.: 23 AF XY: 0.000224 AC XY: 155AN XY: 691794
GnomAD4 genome AF: 0.000604 AC: 92AN: 152318Hom.: 4 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74494
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | RYR2: BP4, BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 26, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 31337358) - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2016 | Variant summary: The RYR2 c.10231-4T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 67/58520 control chromosomes (2 homozygotes) at a frequency of 0.0011449, which is approximately 21 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | - - |
not specified Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Genetic testing: The patient had genetic testing via the Pan Cardio panel with the Ambry laboratory. The test included sequencing of 79 genes associated with hereditary arrhythmias and cardiomyopathies: ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, BAG3, CACNA1C, CACNA2D1, CACNB2, CALR3, CASQ2, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, EYA4, FXN, GATA4, GLA, GPD1L, ILK, JAG1, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ8, KCNQ1, LAMP2, LDB3/ZASP, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2.5, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SGCD, SNTA1, TAZ, TBX1, TBX5, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL. Results reported on April 10th, 2013 show that no disease-causing variants in genes associated with either long QT or hypertrophic cardiomyopathy were found. Testing did identify several variants of uncertain significance: - ANK2 p.Arg996Gln (c.2987G>A, p.R996Q). Ambry classifies this as a variant of uncertain significance. Based on the data reviewed below we consider it a variant of uncertain significance. - ANK2 p.Leu3143Val (c.9427C>G, p.L3143V). Ambry classifies this as a variant of uncertain significance. Based on the data reviewed below we consider it a variant of uncertain significance. -RYR2 c.10231-4T>C. Ambry classifies this as a variant of uncertain significance, suspected benign. Based on the data reviewed below we consider it a variant of uncertain significance, probably benign. The available data on each of these is reviewed below. Given the large number of genes included on this panel and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have. Testing also identified several missense variants in TTN: - TTN c.20722G>A p.V6908I. Ambry classifies this as a variant of uncertain significance. - TTN c.53083A>G p.T17695A. Ambry classifies this as a variant of uncertain significance. - TTN c.71996A>G p.N23999S. Ambry classifies this as a variant, suspected benign. It is unclear at this time what role, if any, TTN missense variants play in causing inherited cardiovascular disease. In general population samples there is a high prevalence of rare or novel TTN missense variants, making it likely that testing anyone with this panel would uncover such a variant. As such we would generally consider all TTN missense variants to be variants of uncertain significance. ANK2 p.Arg996Gln (c.2987G>A, p.R996Q) Ambry classifies this as a variant of uncertain significance. Based on the data reviewed below we consider it a variant of uncertain significance. The variant has not been reported in association with disease but it has been seen in one individual from a general population sample. It is unknown at this time whether this variant and the other ANK2 variant are on the same chromosome or opposite chromosomes. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and SIFT predicts it to be deleterious (per the Ambry report). The arginine at codon 996 is completely conserved across species, as are neighboring amino acids. In total the variant has been seen in 1 of ~7592 individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing P - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 26, 2015 | c.10231-4T>C in intron 70 of RYR2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 1.3% (61/4770) of East Asian chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs117180147). - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 25, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2018 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Arrhythmogenic right ventricular dysplasia 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2016 | This alteration is classified as 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