1-237456575-ATTT-ATTTT

Position:

• chr1-237456575-ATTT-ATTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000366574.7(RYR2):​c.1477-11dup 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 ENST00000366574.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.43

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 -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 [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1477-11dup		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1477-11dup		intron_variant		1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000659194.3	c.1477-11dup		intron_variant				ENSP00000499653
RYR2	ENST00000660292.2	c.1477-11dup		intron_variant				ENSP00000499787
RYR2	ENST00000609119.2	c.1477-11dup		intron_variant, NMD_transcript_variant		5		ENSP00000499659

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

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

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.363

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.379

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

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.546

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.511

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2012	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) -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 16, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		3.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516518; hg19: chr1-237619875;