rs2618713

Variant names:

• chr1-237591888-C-T
• rs2618713
• NM_001035.3:c.4275+35C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.4275+35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,478,018 control chromosomes in the GnomAD database, including 163,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13283 hom., cov: 31)
  • Exomes 𝑓: 0.47 (149899 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.272
• Publications: 10 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=-0.97).
• BP6: Variant 1-237591888-C-T is Benign according to our data. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237591888-C-T is described in CliVar as Benign. Clinvar id is 257211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.4275+35C>T		intron_variant	Intron 32 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.4275+35C>T		intron_variant	Intron 32 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.4275+35C>T		intron_variant	Intron 32 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.4275+35C>T		intron_variant	Intron 32 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59969 AN: 151834 Hom.: 13278 Cov.: 31

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.454 AC: 92391 AN: 203378 AF XY: 0.449

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.470 AC: 623619 AN: 1326066 Hom.: 149899 Cov.: 18 AF XY: 0.467 AC XY: 308904 AN XY: 661788

African (AFR) AF: 0.178 AC: 5460 AN: 30666

American (AMR) AF: 0.597 AC: 23618 AN: 39534

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 11716 AN: 24646

East Asian (EAS) AF: 0.353 AC: 13445 AN: 38062

South Asian (SAS) AF: 0.337 AC: 26823 AN: 79572

European-Finnish (FIN) AF: 0.505 AC: 26121 AN: 51744

Middle Eastern (MID) AF: 0.390 AC: 2147 AN: 5500

European-Non Finnish (NFE) AF: 0.489 AC: 489492 AN: 1000584

Other (OTH) AF: 0.445 AC: 24797 AN: 55758

GnomAD4 genome AF: 0.395 AC: 59975 AN: 151952 Hom.: 13283 Cov.: 31 AF XY: 0.396 AC XY: 29435 AN XY: 74248

African (AFR) AF: 0.196 AC: 8126 AN: 41472

American (AMR) AF: 0.500 AC: 7629 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1623 AN: 3466

East Asian (EAS) AF: 0.325 AC: 1672 AN: 5148

South Asian (SAS) AF: 0.324 AC: 1558 AN: 4810

European-Finnish (FIN) AF: 0.501 AC: 5278 AN: 10532

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32723 AN: 67936

Other (OTH) AF: 0.411 AC: 869 AN: 2116

Alfa AF: 0.442 Hom.: 4149

Bravo AF: 0.391

Asia WGS AF: 0.314 AC: 1092 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 2018

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.97
CADD	Benign	0.21
DANN	Benign	0.67
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2618713; hg19: chr1-237755188; COSMIC: COSV63687171;