rs199562036

Positions:

• chr1-237778782-AACTG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.11880+13_11880+16del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,401,478 control chromosomes in the GnomAD database, including 188 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.014 (170 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0560

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 -16 ACMG points.

• BP6: Variant 1-237778782-AACTG-A is Benign according to our data. Variant chr1-237778782-AACTG-A is described in ClinVar as [Likely_benign]. Clinvar id is 177974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237778782-AACTG-A is described in Lovd as [Benign]. Variant chr1-237778782-AACTG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0106 (1619/152328) while in subpopulation SAS AF= 0.0157 (76/4830). AF 95% confidence interval is 0.0144. There are 18 homozygotes in gnomad4. There are 750 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11880+13_11880+16del		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11880+13_11880+16del		intron_variant		1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000659194.3	c.11868+13_11868+16del		intron_variant				ENSP00000499653
RYR2	ENST00000660292.2	c.11901+13_11901+16del		intron_variant				ENSP00000499787
RYR2	ENST00000609119.2	c.*2972+13_*2972+16del		intron_variant, NMD_transcript_variant		5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1621 AN: 152210 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0111 AC: 2752 AN: 248142 Hom.: 25 AF XY: 0.0119 AC XY: 1596 AN XY: 134624

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00836

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0140 AC: 17543 AN: 1249150 Hom.: 170 AF XY: 0.0141 AC XY: 8942 AN XY: 632182

Gnomad4 AFR exome AF: 0.00247

Gnomad4 AMR exome AF: 0.00833

Gnomad4 ASJ exome AF: 0.00368

Gnomad4 EAS exome AF: 0.0000517

Gnomad4 SAS exome AF: 0.0165

Gnomad4 FIN exome AF: 0.00353

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0106 AC: 1619 AN: 152328 Hom.: 18 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74488

Gnomad4 AFR AF: 0.00305

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0106 Hom.: 0

Bravo AF: 0.0107

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 30, 2013	11880+13_11880+16delACTG in intron 88 of RYR2: This variant is not expected to h ave clinical significance because it is not located within the splice consensus sequence and has been identified in 1.6% (125/7922) of European American chromos omes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2013	The variant is found in ARVC, CPVT, POSTMORTEM, ARRHYTHMIA, CARDIOMYOPATHY panel(s). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: RYR2 c.11880+13_11880+16delACTG alters a 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 248142 control chromosomes in the gnomAD database, including 25 homozygotes. The observed variant frequency is approximately 443 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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: rs199562036; hg19: chr1-237942082; COSMIC: COSV105920987;