rs11583646

Variant names:

• chr1-237643519-G-A
• rs11583646
• NM_001035.3:c.7342+72G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237643519-G-A
• chr1-237643519-G-T

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.7342+72G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,577,024 control chromosomes in the GnomAD database, including 10,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1487 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9181 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.974
• Publications: 5 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=-0.9).
• BP6: Variant 1-237643519-G-A is Benign according to our data. Variant chr1-237643519-G-A is described in ClinVar as Benign. ClinVar VariationId is 1179651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7342+72G>A		intron_variant	Intron 48 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7342+72G>A		intron_variant	Intron 48 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.7342+72G>A		intron_variant	Intron 48 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.7342+72G>A		intron_variant	Intron 48 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19705 AN: 151850 Hom.: 1483 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0831

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.110 AC: 156744 AN: 1425054 Hom.: 9181 AF XY: 0.111 AC XY: 78587 AN XY: 709756

African (AFR) AF: 0.204 AC: 6709 AN: 32808

American (AMR) AF: 0.0555 AC: 2460 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1610 AN: 25622

East Asian (EAS) AF: 0.108 AC: 4229 AN: 39248

South Asian (SAS) AF: 0.144 AC: 12165 AN: 84724

European-Finnish (FIN) AF: 0.0698 AC: 3675 AN: 52674

Middle Eastern (MID) AF: 0.0725 AC: 411 AN: 5668

European-Non Finnish (NFE) AF: 0.110 AC: 118783 AN: 1080976

Other (OTH) AF: 0.114 AC: 6702 AN: 59018

GnomAD4 genome AF: 0.130 AC: 19729 AN: 151970 Hom.: 1487 Cov.: 32 AF XY: 0.127 AC XY: 9425 AN XY: 74262

African (AFR) AF: 0.209 AC: 8680 AN: 41436

American (AMR) AF: 0.0830 AC: 1268 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3468

East Asian (EAS) AF: 0.125 AC: 646 AN: 5176

South Asian (SAS) AF: 0.148 AC: 713 AN: 4814

European-Finnish (FIN) AF: 0.0707 AC: 744 AN: 10522

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7081 AN: 67962

Other (OTH) AF: 0.127 AC: 267 AN: 2110

Alfa AF: 0.111 Hom.: 4087

Bravo AF: 0.133

Asia WGS AF: 0.145 AC: 504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.85
DANN	Benign	0.64
PhyloP100		-0.97
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: rs11583646; hg19: chr1-237806819; COSMIC: COSV63716806;