rs78165942

Variant names:

• chr1-237503283-C-T
• rs78165942
• NM_001035.3:c.2397-6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.2397-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (43 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004965
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.76
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-237503283-C-T is Benign according to our data. Variant chr1-237503283-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0099 (1507/152242) while in subpopulation AFR AF = 0.0323 (1341/41520). AF 95% confidence interval is 0.0309. There are 28 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1507 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.2397-6C>T		splice_region_variant, intron_variant	Intron 21 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.2397-6C>T		splice_region_variant, intron_variant	Intron 21 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.2397-6C>T		splice_region_variant, intron_variant	Intron 21 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.2397-6C>T		splice_region_variant, intron_variant	Intron 21 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00990 AC: 1506 AN: 152124 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00371 AC: 817 AN: 220452 AF XY: 0.00344

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000444

Gnomad FIN exome AF: 0.0000493

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00308

GnomAD4 exome AF: 0.00170 AC: 2455 AN: 1443914 Hom.: 43 Cov.: 31 AF XY: 0.00186 AC XY: 1333 AN XY: 716550

African (AFR) AF: 0.0345 AC: 1143 AN: 33122

American (AMR) AF: 0.00231 AC: 95 AN: 41064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39080

South Asian (SAS) AF: 0.0108 AC: 907 AN: 84040

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52522

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5746

European-Non Finnish (NFE) AF: 0.0000807 AC: 89 AN: 1102696

Other (OTH) AF: 0.00326 AC: 195 AN: 59890

GnomAD4 genome AF: 0.00990 AC: 1507 AN: 152242 Hom.: 28 Cov.: 32 AF XY: 0.00974 AC XY: 725 AN XY: 74446

African (AFR) AF: 0.0323 AC: 1341 AN: 41520

American (AMR) AF: 0.00582 AC: 89 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68046

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00623 Hom.: 10

Bravo AF: 0.0108

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Apr 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jan 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Aug 02, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Jan 12, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.51
PhyloP100		1.8
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0080
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: rs78165942; hg19: chr1-237666583;