1-237506840-A-G

Position:

• chr1-237506840-A-G

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.2718+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 1,571,510 control chromosomes in the GnomAD database, including 355,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38762 hom., cov: 33)
  • Exomes 𝑓: 0.67 (316816 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.316

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]

RYR2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-237506840-A-G is Benign according to our data. Variant chr1-237506840-A-G is described in ClinVar as [Benign]. Clinvar id is 257205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.2718+26A>G		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.2718+26A>G		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.2718+26A>G		intron_variant		5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.2718+26A>G		intron_variant				ENSP00000499787.2
RYR2	ENST00000659194.3	c.2718+26A>G		intron_variant				ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107795 AN: 152046 Hom.: 38713 Cov.: 33

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.657

GnomAD3 exomes AF: 0.666 AC: 159847 AN: 239832 Hom.: 53492 AF XY: 0.662 AC XY: 85834 AN XY: 129666

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.632

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.707

Gnomad SAS exome AF: 0.601

Gnomad FIN exome AF: 0.725

Gnomad NFE exome AF: 0.665

Gnomad OTH exome AF: 0.643

GnomAD4 exome AF: 0.667 AC: 946504 AN: 1419346 Hom.: 316816 Cov.: 22 AF XY: 0.664 AC XY: 469851 AN XY: 707976

Gnomad4 AFR exome AF: 0.839

Gnomad4 AMR exome AF: 0.627

Gnomad4 ASJ exome AF: 0.548

Gnomad4 EAS exome AF: 0.689

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.727

Gnomad4 NFE exome AF: 0.668

Gnomad4 OTH exome AF: 0.664

GnomAD4 genome AF: 0.709 AC: 107900 AN: 152164 Hom.: 38762 Cov.: 33 AF XY: 0.709 AC XY: 52751 AN XY: 74400

Gnomad4 AFR AF: 0.837

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.543

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.726

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.659

Alfa AF: 0.661 Hom.: 56026

Bravo AF: 0.706

Asia WGS AF: 0.692 AC: 2405 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	clinical testing	GeneDx	Jun 18, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.86
CADD	Benign	1.4
DANN	Benign	0.51

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: rs2618702; hg19: chr1-237670140; COSMIC: COSV63672146;