rs2805396

chr1-237569095-G-A

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.3424-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,551,862 control chromosomes in the GnomAD database, including 363,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28394 hom., cov: 30)
  • Exomes 𝑓: 0.69 (335014 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.329

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=-0.84).
• BP6: Variant 1-237569095-G-A is Benign according to our data. Variant chr1-237569095-G-A is described in ClinVar as [Benign]. Clinvar id is 257208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3424-50G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3424-50G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.3424-50G>A		intron_variant
RYR2	ENST00000660292.2	c.3424-50G>A		intron_variant
RYR2	ENST00000609119.2	c.3424-50G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88360 AN: 151684 Hom.: 28378 Cov.: 30

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.628

Gnomad NFE AF: 0.710

Gnomad OTH AF: 0.610

GnomAD3 exomes AF: 0.648 AC: 139415 AN: 215306 Hom.: 47621 AF XY: 0.656 AC XY: 75948 AN XY: 115768

Gnomad AFR exome AF: 0.307

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.264

Gnomad SAS exome AF: 0.679

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.713

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.685 AC: 959238 AN: 1400060 Hom.: 335014 Cov.: 23 AF XY: 0.687 AC XY: 474151 AN XY: 689832

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.738

Gnomad4 ASJ exome AF: 0.777

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.685

Gnomad4 FIN exome AF: 0.670

Gnomad4 NFE exome AF: 0.709

Gnomad4 OTH exome AF: 0.657

GnomAD4 genome AF: 0.582 AC: 88408 AN: 151802 Hom.: 28394 Cov.: 30 AF XY: 0.581 AC XY: 43086 AN XY: 74174

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.692

Gnomad4 ASJ AF: 0.777

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.667

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.710

Gnomad4 OTH AF: 0.610

Alfa AF: 0.663 Hom.: 6481

Bravo AF: 0.573

Asia WGS AF: 0.474 AC: 1650 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	-0.84
Cadd	Benign	0.27
Dann	Benign	0.79

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: rs2805396; hg19: chr1-237732395; COSMIC: COSV63673625;