rs2779430

chr1-237591903-T-C

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+50T>C 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 1,306,238 control chromosomes in the GnomAD database, including 143,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13463 hom., cov: 31)
  • Exomes 𝑓: 0.47 (130351 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.610

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=-0.9).
• BP6: Variant 1-237591903-T-C is Benign according to our data. Variant chr1-237591903-T-C is described in ClinVar as [Benign]. Clinvar id is 257212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4275+50T>C		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4275+50T>C		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.4275+50T>C		intron_variant
RYR2	ENST00000660292.2	c.4275+50T>C		intron_variant
RYR2	ENST00000609119.2	c.4275+50T>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60392 AN: 151916 Hom.: 13459 Cov.: 31

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.424

GnomAD3 exomes AF: 0.455 AC: 82759 AN: 181900 Hom.: 19986 AF XY: 0.450 AC XY: 43402 AN XY: 96440

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.478

GnomAD4 exome AF: 0.472 AC: 544634 AN: 1154204 Hom.: 130351 Cov.: 15 AF XY: 0.468 AC XY: 272265 AN XY: 581534

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.598

Gnomad4 ASJ exome AF: 0.478

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.506

Gnomad4 NFE exome AF: 0.491

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.397 AC: 60397 AN: 152034 Hom.: 13463 Cov.: 31 AF XY: 0.399 AC XY: 29617 AN XY: 74304

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.471

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.419

Alfa AF: 0.444 Hom.: 4199

Bravo AF: 0.395

Asia WGS AF: 0.317 AC: 1103 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	-0.90
Cadd	Benign	1.8
Dann	Benign	0.41

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: rs2779430; hg19: chr1-237755203; COSMIC: COSV63689427;