rs577119352

Positions:

• chr1-237742286-A-T

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.11092-10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,239,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.00002492
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.00

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=-0.88).
• BP6: Variant 1-237742286-A-T is Benign according to our data. Variant chr1-237742286-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 296751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00023 (285/1239728) while in subpopulation AMR AF= 0.000839 (20/23834). AF 95% confidence interval is 0.000555. There are 0 homozygotes in gnomad4_exome. There are 140 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 285 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11092-10A>T		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11092-10A>T		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.1	c.898-10A>T		intron_variant				ENSP00000499393.2
RYR2	ENST00000609119.2	n.*2127-10A>T		intron_variant		5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 24 AN: 140732 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.000225

Gnomad FIN AF: 0.000583

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000589 AC: 57 AN: 96760 Hom.: 0 AF XY: 0.000627 AC XY: 32 AN XY: 51068

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.000488

Gnomad EAS exome AF: 0.00176

Gnomad SAS exome AF: 0.000387

Gnomad FIN exome AF: 0.000778

Gnomad NFE exome AF: 0.000456

Gnomad OTH exome AF: 0.000780

GnomAD4 exome AF: 0.000230 AC: 285 AN: 1239728 Hom.: 0 Cov.: 26 AF XY: 0.000228 AC XY: 140 AN XY: 614248

Gnomad4 AFR exome AF: 0.000654

Gnomad4 AMR exome AF: 0.000839

Gnomad4 ASJ exome AF: 0.000222

Gnomad4 EAS exome AF: 0.000485

Gnomad4 SAS exome AF: 0.000261

Gnomad4 FIN exome AF: 0.000248

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000170 AC: 24 AN: 140818 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 12 AN XY: 68220

Gnomad4 AFR AF: 0.000158

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00101

Gnomad4 SAS AF: 0.000225

Gnomad4 FIN AF: 0.000583

Gnomad4 NFE AF: 0.000109

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 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. -

Catecholaminergic polymorphic ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 17, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2;C5542154:Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

RYR2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	-0.88
CADD	Benign	0.21
DANN	Benign	0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.012
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: rs577119352; hg19: chr1-237905586;