rs193922621

chr1-237441447-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001035.3(RYR2):c.1134C>T(p.Asp378=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000831 in 1,596,894 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (5 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.807

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-237441447-C-T is Benign according to our data. Variant chr1-237441447-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237441447-C-T is described in Lovd as [Likely_benign]. Variant chr1-237441447-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.807 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000717 (109/152096) while in subpopulation NFE AF= 0.00129 (88/68000). AF 95% confidence interval is 0.00108. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.1134C>T	p.Asp378=	synonymous_variant	13/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.1134C>T	p.Asp378=	synonymous_variant	13/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.1134C>T	p.Asp378=	synonymous_variant	13/106
RYR2	ENST00000659194.3	c.1134C>T	p.Asp378=	synonymous_variant	13/105
RYR2	ENST00000609119.2	c.1134C>T	p.Asp378=	synonymous_variant, NMD_transcript_variant	13/104	5

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 151978 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000590 AC: 143 AN: 242522 Hom.: 0 AF XY: 0.000540 AC XY: 71 AN XY: 131474

Gnomad AFR exome AF: 0.0000660

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000227

Gnomad SAS exome AF: 0.0000340

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000516

GnomAD4 exome AF: 0.000843 AC: 1218 AN: 1444798 Hom.: 5 Cov.: 30 AF XY: 0.000818 AC XY: 587 AN XY: 717754

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000296

Gnomad4 ASJ exome AF: 0.000196

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.000360

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000536

GnomAD4 genome AF: 0.000717 AC: 109 AN: 152096 Hom.: 1 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74350

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000851

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000854 Hom.: 1

Bravo AF: 0.000548

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RYR2: BP4, BP7, BS1 -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	p.Asp378Asp in exon 13 of RYR2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.1% (69/66454) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs193922621). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 31, 2017	- -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

RYR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2017

This alteration is classified as likely 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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	4.0
Dann	Benign	0.46

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: rs193922621; hg19: chr1-237604747; COSMIC: COSV100770864;