rs10802626

Positions:

• chr1-237633537-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.6556-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,610,230 control chromosomes in the GnomAD database, including 102,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12271 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90720 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.235

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=-0.92).
• BP6: Variant 1-237633537-G-A is Benign according to our data. Variant chr1-237633537-G-A is described in ClinVar as [Benign]. Clinvar id is 257214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.6556-41G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.6556-41G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.6556-41G>A		intron_variant
RYR2	ENST00000660292.2	c.6556-41G>A		intron_variant
RYR2	ENST00000609119.2	c.6556-41G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59993 AN: 151868 Hom.: 12238 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.362 AC: 89803 AN: 248406 Hom.: 16810 AF XY: 0.356 AC XY: 48001 AN XY: 134812

Gnomad AFR exome AF: 0.513

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.465

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.350 AC: 509664 AN: 1458244 Hom.: 90720 Cov.: 31 AF XY: 0.349 AC XY: 252758 AN XY: 725216

Gnomad4 AFR exome AF: 0.507

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.431

Gnomad4 SAS exome AF: 0.349

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.395 AC: 60080 AN: 151986 Hom.: 12271 Cov.: 32 AF XY: 0.393 AC XY: 29220 AN XY: 74276

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.459

Gnomad4 SAS AF: 0.362

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.373

Alfa AF: 0.342 Hom.: 11269

Bravo AF: 0.405

Asia WGS AF: 0.457 AC: 1588 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.92
CADD	Benign	1.8
DANN	Benign	0.55

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: rs10802626; hg19: chr1-237796837; COSMIC: COSV63687186;