rs2618713

chr1-237591888-C-T

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.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:2
• Conservation: PhyloP100: -0.272

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=-0.97).
• BP6: Variant 1-237591888-C-T is Benign according to our data. Variant chr1-237591888-C-T is described in ClinVar 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/exons	MANE	UniProt
RYR2	NM_001035.3	c.4275+35C>T		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4275+35C>T		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.4275+35C>T		intron_variant
RYR2	ENST00000660292.2	c.4275+35C>T		intron_variant
RYR2	ENST00000609119.2	c.4275+35C>T		intron_variant, NMD_transcript_variant		5

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

GnomAD3 exomes AF: 0.454 AC: 92391 AN: 203378 Hom.: 22071 AF XY: 0.449 AC XY: 48820 AN XY: 108704

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 SAS exome AF: 0.342

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

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.597

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.489

Gnomad4 OTH exome AF: 0.445

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

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.411

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.21
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2618713; hg19: chr1-237755188; COSMIC: COSV63687171;