rs16835237

chr1-237423084-T-C

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.849-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,609,586 control chromosomes in the GnomAD database, including 11,647 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1118 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10529 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008724
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.429

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=-0.72).
• BP6: Variant 1-237423084-T-C is Benign according to our data. Variant chr1-237423084-T-C is described in ClinVar as [Benign]. Clinvar id is 43834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237423084-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.849-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.849-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.849-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000660292.2	c.849-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000609119.2	c.849-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15847 AN: 152082 Hom.: 1123 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0946

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.147 AC: 36047 AN: 245086 Hom.: 3720 AF XY: 0.141 AC XY: 18777 AN XY: 132986

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.309

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.0904

Gnomad NFE exome AF: 0.0990

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.108 AC: 156751 AN: 1457386 Hom.: 10529 Cov.: 31 AF XY: 0.109 AC XY: 78877 AN XY: 724848

Gnomad4 AFR exome AF: 0.0626

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.0925

Gnomad4 NFE exome AF: 0.0930

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.104 AC: 15862 AN: 152200 Hom.: 1118 Cov.: 32 AF XY: 0.107 AC XY: 7963 AN XY: 74404

Gnomad4 AFR AF: 0.0643

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0844

Gnomad4 NFE AF: 0.0946

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0998 Hom.: 1368

Bravo AF: 0.114

Asia WGS AF: 0.195 AC: 675 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2012	849-8T>C in Intron 11 of RYR2: This variant has been classified as benign based on high population frequency (MAF=0.164, rs16835237) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 09, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	12
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.10		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: rs16835237; hg19: chr1-237586384; COSMIC: COSV63663128;