rs9428384

chr1-237801831-G-Achr1-237801831-G-Cchr1-237801831-G-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.14091-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,447,184 control chromosomes in the GnomAD database, including 121,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10781 hom., cov: 31)
  • Exomes 𝑓: 0.41 (111009 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0840

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=-0.96).
• BP6: Variant 1-237801831-G-A is Benign according to our data. Variant chr1-237801831-G-A is described in ClinVar as [Benign]. Clinvar id is 257203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.14091-25G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.14091-25G>A		intron_variant		1	NM_001035.3	P1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 54808 AN: 149540 Hom.: 10778 Cov.: 31

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.389

GnomAD3 exomes AF: 0.413 AC: 93115 AN: 225654 Hom.: 20387 AF XY: 0.418 AC XY: 51427 AN XY: 123144

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.478

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.407 AC: 527615 AN: 1297538 Hom.: 111009 Cov.: 19 AF XY: 0.410 AC XY: 265680 AN XY: 648240

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.494

Gnomad4 EAS exome AF: 0.643

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.398

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.366 AC: 54823 AN: 149646 Hom.: 10781 Cov.: 31 AF XY: 0.368 AC XY: 26930 AN XY: 73082

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.483

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.390

Alfa AF: 0.386 Hom.: 1749

Bravo AF: 0.354

Asia WGS AF: 0.495 AC: 1711 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 18, 2019

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	4.4
Dann	Benign	0.48

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: rs9428384; hg19: chr1-237965131;