rs41267519

chr1-237808889-A-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.14299-12A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,613,024 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (77 hom.)
• Consequence: RYR2 NM_001035.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004738
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.472

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=-0.68).
• BP6: Variant 1-237808889-A-G is Benign according to our data. Variant chr1-237808889-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 43740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237808889-A-G is described in Lovd as [Benign]. Variant chr1-237808889-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00652 (992/152232) while in subpopulation SAS AF= 0.0205 (99/4818). AF 95% confidence interval is 0.0173. There are 11 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 992 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.14299-12A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.14299-12A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	P1

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152114 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00837 AC: 2085 AN: 249208 Hom.: 18 AF XY: 0.00940 AC XY: 1271 AN XY: 135212

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.00896

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00850 AC: 12413 AN: 1460792 Hom.: 77 Cov.: 30 AF XY: 0.00896 AC XY: 6514 AN XY: 726732

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.00834

Gnomad4 OTH exome AF: 0.00822

GnomAD4 genome AF: 0.00652 AC: 992 AN: 152232 Hom.: 11 Cov.: 33 AF XY: 0.00653 AC XY: 486 AN XY: 74432

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00847

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00704 Hom.: 3

Bravo AF: 0.00626

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2015	c.14299-12A>G in intron 99 of RYR2: This variant is not expected to have clinica l significance because it has been identified in 2.4% (395/16510) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs41267519). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: RYR2 c.14299-12A>G 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 0.0084 in 249208 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 334 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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 15, 2018

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Likely 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 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	-0.68
Cadd	Benign	0.33
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.024
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: rs41267519; hg19: chr1-237972189;