rs2253831

Variant names:

• chr1-237759753-C-T
• rs2253831
• NM_001035.3:c.11326-23C>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.11326-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,483,426 control chromosomes in the GnomAD database, including 363,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40736 hom., cov: 31)
  • Exomes 𝑓: 0.70 (322854 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0510
• Publications: 11 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=-0.68).
• BP6: Variant 1-237759753-C-T is Benign according to our data. Variant chr1-237759753-C-T is described in ClinVar as Benign. ClinVar VariationId is 257198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11326-23C>T		intron_variant	Intron 82 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11326-23C>T		intron_variant	Intron 82 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.11350-23C>T		intron_variant	Intron 83 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*2418-23C>T		intron_variant	Intron 81 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110940 AN: 151880 Hom.: 40687 Cov.: 31

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.755

GnomAD2 exomes AF: 0.713 AC: 177132 AN: 248294 AF XY: 0.709

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.738

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.779

Gnomad FIN exome AF: 0.740

Gnomad NFE exome AF: 0.683

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.695 AC: 925643 AN: 1331426 Hom.: 322854 Cov.: 20 AF XY: 0.695 AC XY: 465194 AN XY: 669826

African (AFR) AF: 0.796 AC: 24509 AN: 30772

American (AMR) AF: 0.740 AC: 32866 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 18113 AN: 25308

East Asian (EAS) AF: 0.793 AC: 31004 AN: 39082

South Asian (SAS) AF: 0.703 AC: 58798 AN: 83592

European-Finnish (FIN) AF: 0.735 AC: 39158 AN: 53304

Middle Eastern (MID) AF: 0.747 AC: 4114 AN: 5508

European-Non Finnish (NFE) AF: 0.682 AC: 677181 AN: 993486

Other (OTH) AF: 0.713 AC: 39900 AN: 55942

GnomAD4 genome AF: 0.731 AC: 111041 AN: 152000 Hom.: 40736 Cov.: 31 AF XY: 0.736 AC XY: 54680 AN XY: 74288

African (AFR) AF: 0.794 AC: 32916 AN: 41468

American (AMR) AF: 0.744 AC: 11357 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2509 AN: 3472

East Asian (EAS) AF: 0.789 AC: 4060 AN: 5144

South Asian (SAS) AF: 0.700 AC: 3361 AN: 4804

European-Finnish (FIN) AF: 0.753 AC: 7950 AN: 10564

Middle Eastern (MID) AF: 0.779 AC: 226 AN: 290

European-Non Finnish (NFE) AF: 0.683 AC: 46419 AN: 67968

Other (OTH) AF: 0.757 AC: 1598 AN: 2110

Alfa AF: 0.706 Hom.: 14031

Bravo AF: 0.730

Asia WGS AF: 0.769 AC: 2677 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Nov 07, 2021

Genome-Nilou Lab

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	-0.68
CADD	Benign	2.5
DANN	Benign	0.79
PhyloP100		-0.051
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2253831; hg19: chr1-237923053;