rs74323916

chr1-237709587-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):c.10230+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,519,598 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (160 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.618

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=-0.85).
• BP6: Variant 1-237709587-T-C is Benign according to our data. Variant chr1-237709587-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 36728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237709587-T-C is described in Lovd as [Benign]. Variant chr1-237709587-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0114 (1736/152212) while in subpopulation AMR AF= 0.0157 (240/15292). AF 95% confidence interval is 0.0141. There are 19 homozygotes in gnomad4. There are 800 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1731 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.10230+20T>C		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.10230+20T>C		intron_variant		1	NM_001035.3	P1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1731 AN: 152094 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00616

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0112 AC: 2493 AN: 222208 Hom.: 19 AF XY: 0.0119 AC XY: 1425 AN XY: 119416

Gnomad AFR exome AF: 0.00464

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.00974

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.00271

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0142 AC: 19426 AN: 1367386 Hom.: 160 Cov.: 20 AF XY: 0.0143 AC XY: 9746 AN XY: 683224

Gnomad4 AFR exome AF: 0.00567

Gnomad4 AMR exome AF: 0.00844

Gnomad4 ASJ exome AF: 0.00824

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.00327

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0114 AC: 1736 AN: 152212 Hom.: 19 Cov.: 32 AF XY: 0.0107 AC XY: 800 AN XY: 74426

Gnomad4 AFR AF: 0.00626

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0108 Hom.: 1

Bravo AF: 0.0115

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: RYR2 c.10230+20T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.011 in 222208 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 187 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.3
Dann	Benign	0.39

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: rs74323916; hg19: chr1-237872887;