1-237711741-T-C

Variant names:

• chr1-237711741-T-C
• rs117180147
• NM_001035.3:c.10231-4T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):​c.10231-4T>C variant causes a splice region, 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:
  • Genomes: 𝑓 0.00060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004187
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: -0.0530
• Publications: 5 publications found

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-237711741-T-C is Benign according to our data. Variant chr1-237711741-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167631.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000604 (92/152318) while in subpopulation EAS AF = 0.00945 (49/5184). AF 95% confidence interval is 0.00735. There are 4 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.10231-4T>C		splice_region_variant, intron_variant	Intron 70 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.10231-4T>C		splice_region_variant, intron_variant	Intron 70 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.10231-4T>C		splice_region_variant, intron_variant	Intron 70 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*1266-4T>C		splice_region_variant, intron_variant	Intron 68 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152200 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000726 AC: 165 AN: 227240 AF XY: 0.000620

Gnomad AFR exome AF: 0.000511

Gnomad AMR exome AF: 0.0000624

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00899

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000709

GnomAD4 exome AF: 0.000230 AC: 319 AN: 1386568 Hom.: 2 Cov.: 23 AF XY: 0.000224 AC XY: 155 AN XY: 691794

African (AFR) AF: 0.000156 AC: 5 AN: 32042

American (AMR) AF: 0.0000469 AC: 2 AN: 42660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00518 AC: 203 AN: 39192

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00000381 AC: 4 AN: 1049982

Other (OTH) AF: 0.00179 AC: 103 AN: 57654

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152318 Hom.: 4 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74494

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.00203 AC: 31 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000472

Asia WGS AF: 0.00751 AC: 26 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 26, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31337358) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR2: BP4, BS1, BS2 -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 -

Jun 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 29, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		-0.053
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117180147; hg19: chr1-237875041;