rs147479514

Positions:

• chr1-237500704-C-G

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.2204-7C>G 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 0.011 in 1,589,644 control chromosomes in the GnomAD database, including 136 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (12 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003871
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.0540

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=-0.79).
• BP6: Variant 1-237500704-C-G is Benign according to our data. Variant chr1-237500704-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 36738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237500704-C-G is described in Lovd as [Benign]. Variant chr1-237500704-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00914 (1391/152250) while in subpopulation NFE AF= 0.0132 (896/67996). AF 95% confidence interval is 0.0125. There are 12 homozygotes in gnomad4. There are 717 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1391 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2204-7C>G		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.2204-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.2204-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000660292.2	c.2204-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RYR2	ENST00000609119.2	c.2204-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1391 AN: 152132 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00959 AC: 2307 AN: 240644 Hom.: 20 AF XY: 0.00962 AC XY: 1253 AN XY: 130236

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00550

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0133

GnomAD4 exome AF: 0.0112 AC: 16137 AN: 1437394 Hom.: 124 Cov.: 31 AF XY: 0.0110 AC XY: 7847 AN XY: 711204

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.000277

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00563

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00914 AC: 1391 AN: 152250 Hom.: 12 Cov.: 32 AF XY: 0.00963 AC XY: 717 AN XY: 74458

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0115 Hom.: 4

Bravo AF: 0.00734

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RYR2: BP4, BS1, BS2 -

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	Apr 03, 2012	2204-7C>G in intron 20 of RYR2: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence and ha s been identified in 1.2% (78/6636) of European American chromosomes and 3/3058 African American chromosomes from a broad, though clinically unspecified populat ion (dbSNP rs147479514, NHLBI Exome Sequencing Project; http://evs.gs.washington .edu/EVS). 2204-7C>G in intron 20 of RYR2 (rs147479514, NHLBI Exome Seq Project ; 1.2%,78/6636) -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 17, 2017	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 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. -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.010		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: rs147479514; hg19: chr1-237664004;