1-237388076-T-A

Variant names:

• chr1-237388076-T-A
• rs10754602
• NM_001035.3:c.677-11T>A

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.677-11T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 1,610,562 control chromosomes in the GnomAD database, including 255,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23035 hom., cov: 33)
  • Exomes 𝑓: 0.56 (232849 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.0001482
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.54

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=-0.9).
• BP6: Variant 1-237388076-T-A is Benign according to our data. Variant chr1-237388076-T-A is described in ClinVar as [Benign]. Clinvar id is 43817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237388076-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.677-11T>A		intron_variant	Intron 9 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.677-11T>A		intron_variant	Intron 9 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.677-11T>A		intron_variant	Intron 9 of 103	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.677-11T>A		intron_variant	Intron 9 of 105			ENSP00000499787.2
RYR2	ENST00000659194.3	c.677-11T>A		intron_variant	Intron 9 of 104			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.546 AC: 83008 AN: 152052 Hom.: 23013 Cov.: 33

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.576 AC: 142200 AN: 247080 Hom.: 41956 AF XY: 0.565 AC XY: 75689 AN XY: 133972

Gnomad AFR exome AF: 0.452

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.634

Gnomad SAS exome AF: 0.462

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.565

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.563 AC: 820992 AN: 1458390 Hom.: 232849 Cov.: 32 AF XY: 0.560 AC XY: 405938 AN XY: 725426

Gnomad4 AFR exome AF: 0.452

Gnomad4 AMR exome AF: 0.759

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.642

Gnomad4 SAS exome AF: 0.467

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.565

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.546 AC: 83068 AN: 152172 Hom.: 23035 Cov.: 33 AF XY: 0.544 AC XY: 40477 AN XY: 74392

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.629

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.567

Alfa AF: 0.476 Hom.: 2502

Bravo AF: 0.558

Asia WGS AF: 0.582 AC: 2024 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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

- -

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

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. -

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

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Arrhythmogenic right ventricular dysplasia 2 Benign:2

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 08, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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	-0.90
CADD	Benign	4.0
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10754602; hg19: chr1-237551376;