rs141528541

chr1-237784986-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.13260+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,532,162 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (108 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0330

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_addAF=-0.713467).
• BP6: Variant 1-237784986-A-G is Benign according to our data. Variant chr1-237784986-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 36732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237784986-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00764 (1164/152270) while in subpopulation SAS AF= 0.0247 (119/4818). AF 95% confidence interval is 0.0211. There are 14 homozygotes in gnomad4. There are 552 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.13260+14A>G		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.13260+14A>G		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.13248+14A>G		intron_variant
RYR2	ENST00000660292.2	c.13281+14A>G		intron_variant
RYR2	ENST00000609119.2	c.*4352+14A>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152152 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00984

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00926 AC: 1488 AN: 160766 Hom.: 14 AF XY: 0.0103 AC XY: 881 AN XY: 85816

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00535

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0107 AC: 14731 AN: 1379892 Hom.: 108 Cov.: 25 AF XY: 0.0109 AC XY: 7478 AN XY: 683478

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00532

Gnomad4 ASJ exome AF: 0.00534

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.00764 AC: 1164 AN: 152270 Hom.: 14 Cov.: 32 AF XY: 0.00741 AC XY: 552 AN XY: 74452

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00985

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00732 Hom.: 0

Bravo AF: 0.00736

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00187 AC: 7

ESP6500EA AF: 0.00916 AC: 75

ExAC AF: 0.00670 AC: 775

Asia WGS AF: 0.0110 AC: 39 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2012	- -
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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -
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	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 13, 2015

- -

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_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.98
Dann	Benign	0.63
FATHMM_MKL	Benign	0.023	N
MutationTaster	Benign	1.0	N
GERP RS		-0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs141528541; hg19: chr1-237948286;