rs114289907

chr1-237792064-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.13564-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,414,876 control chromosomes in the GnomAD database, including 1,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (135 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1254 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.256

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=-0.81).
• BP6: Variant 1-237792064-A-G is Benign according to our data. Variant chr1-237792064-A-G is described in ClinVar as [Benign]. Clinvar id is 218487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237792064-A-G is described in Lovd as [Benign]. Variant chr1-237792064-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.13564-41A>G		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.13564-41A>G		intron_variant		1	NM_001035.3	P1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6171 AN: 152006 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0330

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0436 AC: 7058 AN: 161706 Hom.: 249 AF XY: 0.0480 AC XY: 4093 AN XY: 85328

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0352

Gnomad EAS exome AF: 0.0303

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0364 AC: 45985 AN: 1262752 Hom.: 1254 Cov.: 18 AF XY: 0.0389 AC XY: 24544 AN XY: 630476

Gnomad4 AFR exome AF: 0.0575

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0357

Gnomad4 EAS exome AF: 0.0214

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0424

GnomAD4 genome AF: 0.0406 AC: 6175 AN: 152124 Hom.: 135 Cov.: 32 AF XY: 0.0413 AC XY: 3072 AN XY: 74360

Gnomad4 AFR AF: 0.0544

Gnomad4 AMR AF: 0.0329

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.0340

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.0322

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0380 Hom.: 36

Bravo AF: 0.0415

Asia WGS AF: 0.0660 AC: 228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.8
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs114289907; hg19: chr1-237955364; COSMIC: COSV63707450;