1-237793861-A-G

Variant names:

• chr1-237793861-A-G
• rs790901
• NM_001035.3:c.13783-6A>G

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.13783-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,589,870 control chromosomes in the GnomAD database, including 391,473 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 0.68 (35626 hom., cov: 32)
  • Exomes 𝑓: 0.70 (355847 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.000008101
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.42

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=-0.81).
• BP6: Variant 1-237793861-A-G is Benign according to our data. Variant chr1-237793861-A-G is described in ClinVar as [Benign]. Clinvar id is 43731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237793861-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.13783-6A>G		splice_region_variant, intron_variant	Intron 94 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.13783-6A>G		splice_region_variant, intron_variant	Intron 94 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.*4875-6A>G		splice_region_variant, intron_variant	Intron 93 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103170 AN: 151848 Hom.: 35604 Cov.: 32

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.655

GnomAD3 exomes AF: 0.738 AC: 180422 AN: 244512 Hom.: 67893 AF XY: 0.739 AC XY: 97904 AN XY: 132442

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.825

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.947

Gnomad SAS exome AF: 0.862

Gnomad FIN exome AF: 0.708

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.699 AC: 1005342 AN: 1437904 Hom.: 355847 Cov.: 28 AF XY: 0.704 AC XY: 504058 AN XY: 716162

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.818

Gnomad4 ASJ exome AF: 0.655

Gnomad4 EAS exome AF: 0.950

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.703

Gnomad4 NFE exome AF: 0.677

Gnomad4 OTH exome AF: 0.697

GnomAD4 genome AF: 0.679 AC: 103237 AN: 151966 Hom.: 35626 Cov.: 32 AF XY: 0.686 AC XY: 50928 AN XY: 74280

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.750

Gnomad4 ASJ AF: 0.642

Gnomad4 EAS AF: 0.954

Gnomad4 SAS AF: 0.862

Gnomad4 FIN AF: 0.696

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.658

Alfa AF: 0.674 Hom.: 44424

Bravo AF: 0.678

Asia WGS AF: 0.877 AC: 3046 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Arrhythmogenic right ventricular dysplasia 2 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiac arrhythmia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000081
dbscSNV1_RF	Benign	0.0
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: rs790901; hg19: chr1-237957161;