1-237456575-ATTTT-ATTTTT

Variant names:

• chr1-237456575-A-AT
• rs397516518
• NM_001035.3:c.1477-11dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.1477-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.53 (20698 hom., cov: 0)
  • Exomes 𝑓: 0.38 (1405 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.43
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 1-237456575-A-AT is Benign according to our data. Variant chr1-237456575-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1477-11dupT		intron_variant	Intron 15 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1477-25_1477-24insT		intron_variant	Intron 15 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.1477-25_1477-24insT		intron_variant	Intron 15 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.1477-25_1477-24insT		intron_variant	Intron 15 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.528 AC: 78611 AN: 148976 Hom.: 20702 Cov.: 0

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.379 AC: 53902 AN: 142038 AF XY: 0.378

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.383

Gnomad OTH exome AF: 0.365

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.384 AC: 460749 AN: 1198394 Hom.: 1405 Cov.: 0 AF XY: 0.383 AC XY: 223788 AN XY: 584872

African (AFR) AF: 0.340 AC: 8745 AN: 25734

American (AMR) AF: 0.363 AC: 8846 AN: 24344

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 7052 AN: 19366

East Asian (EAS) AF: 0.445 AC: 14188 AN: 31882

South Asian (SAS) AF: 0.337 AC: 16941 AN: 50240

European-Finnish (FIN) AF: 0.365 AC: 13668 AN: 37412

Middle Eastern (MID) AF: 0.353 AC: 1651 AN: 4678

European-Non Finnish (NFE) AF: 0.388 AC: 371284 AN: 956292

Other (OTH) AF: 0.379 AC: 18374 AN: 48446

GnomAD4 genome AF: 0.528 AC: 78635 AN: 149056 Hom.: 20698 Cov.: 0 AF XY: 0.529 AC XY: 38362 AN XY: 72500

African (AFR) AF: 0.469 AC: 19086 AN: 40732

American (AMR) AF: 0.544 AC: 8138 AN: 14962

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1885 AN: 3454

East Asian (EAS) AF: 0.682 AC: 3433 AN: 5032

South Asian (SAS) AF: 0.536 AC: 2526 AN: 4714

European-Finnish (FIN) AF: 0.542 AC: 5206 AN: 9608

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.544 AC: 36608 AN: 67296

Other (OTH) AF: 0.511 AC: 1051 AN: 2058

Alfa AF: 0.461 Hom.: 648

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1477-11_1477-10insT in intron 15 of RYR2: This variant is not expected to have c linical significance because it is located outside the conserved +/- 1, 2 region of the splicing consensus sequence and is part of a polyT stretch. 1477-11_147 7-10insT in intron 15 of RYR2 (allele frequency = n/a) -

Aug 19, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.1477-11dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.4 in 170484 control chromosomes in the gnomAD database, including 3845 homozygotes. The observed variant frequency is approximately 16047-folds over the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Oct 16, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 15, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
BranchPoint Hunter		3.0
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: rs397516518; hg19: chr1-237619875;