rs11583646

chr1-237643519-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.974

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 -14 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 id is 1179651.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
RYR2	NM_001035.3	c.7342+72G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.7342+72G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.7342+72G>A		intron_variant
RYR2	ENST00000660292.2	c.7342+72G>A		intron_variant
RYR2	ENST00000609119.2	c.7342+72G>A		intron_variant, NMD_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.0555

Gnomad4 ASJ exome AF: 0.0628

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0698

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.114

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

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.0707

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.127

Alfa AF: 0.108 Hom.: 1806

Bravo AF: 0.133

Asia WGS AF: 0.145 AC: 504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.85
Dann	Benign	0.64

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: rs11583646; hg19: chr1-237806819; COSMIC: COSV63716806;