1-237506840-A-G

Variant names:

• chr1-237506840-A-G
• rs2618702
• NM_001035.3:c.2718+26A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.2718+26A>G		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.2718+26A>G		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.2718+26A>G		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.2718+26A>G		intron	N/A	ENSP00000499659.2

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

GnomAD2 exomes AF: 0.666 AC: 159847 AN: 239832 AF XY: 0.662

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 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

African (AFR) AF: 0.839 AC: 27419 AN: 32676

American (AMR) AF: 0.627 AC: 27437 AN: 43774

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 14087 AN: 25706

East Asian (EAS) AF: 0.689 AC: 27176 AN: 39420

South Asian (SAS) AF: 0.600 AC: 50662 AN: 84380

European-Finnish (FIN) AF: 0.727 AC: 38556 AN: 53056

Middle Eastern (MID) AF: 0.611 AC: 3467 AN: 5670

European-Non Finnish (NFE) AF: 0.668 AC: 718543 AN: 1075680

Other (OTH) AF: 0.664 AC: 39157 AN: 58984

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

African (AFR) AF: 0.837 AC: 34751 AN: 41528

American (AMR) AF: 0.634 AC: 9697 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1883 AN: 3468

East Asian (EAS) AF: 0.702 AC: 3628 AN: 5168

South Asian (SAS) AF: 0.593 AC: 2865 AN: 4828

European-Finnish (FIN) AF: 0.726 AC: 7684 AN: 10582

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45204 AN: 67992

Other (OTH) AF: 0.659 AC: 1389 AN: 2108

Alfa AF: 0.672 Hom.: 134316

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

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiac arrhythmia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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