chr1-237783664-T-C

Variant names:

• chr1-237783664-T-C
• rs790889
• NM_001035.3:c.11963-11T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.11963-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,562,038 control chromosomes in the GnomAD database, including 99,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9870 hom., cov: 33)
  • Exomes 𝑓: 0.35 (89859 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.001738
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.41

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-237783664-T-C is Benign according to our data. Variant chr1-237783664-T-C is described in ClinVar as [Benign]. Clinvar id is 43716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237783664-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11963-11T>C		intron_variant	Intron 89 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11963-11T>C		intron_variant	Intron 89 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*3055-11T>C		intron_variant	Intron 88 of 103	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.11984-11T>C		intron_variant	Intron 90 of 105			ENSP00000499787.2
RYR2	ENST00000659194.3	c.11951-11T>C		intron_variant	Intron 89 of 104			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53570 AN: 152004 Hom.: 9855 Cov.: 33

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.383 AC: 83586 AN: 218184 Hom.: 16728 AF XY: 0.382 AC XY: 44825 AN XY: 117202

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.665

Gnomad SAS exome AF: 0.425

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.350 AC: 492775 AN: 1409916 Hom.: 89859 Cov.: 26 AF XY: 0.352 AC XY: 245422 AN XY: 697400

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.693

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.352 AC: 53622 AN: 152122 Hom.: 9870 Cov.: 33 AF XY: 0.356 AC XY: 26486 AN XY: 74342

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.377

Gnomad4 ASJ AF: 0.429

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.349

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.361

Alfa AF: 0.306 Hom.: 1917

Bravo AF: 0.353

Asia WGS AF: 0.513 AC: 1784 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Sep 15, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:3

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Cardiomyopathy Benign:1

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs790889; hg19: chr1-237946964; COSMIC: COSV63674062;