rs113408406

Positions:

• chr1-237770906-C-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.11557+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,475,274 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (46 hom., cov: 32)
  • Exomes 𝑓: 0.026 (574 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.88

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=-0.87).
• BP6: Variant 1-237770906-C-T is Benign according to our data. Variant chr1-237770906-C-T is described in ClinVar as [Benign]. Clinvar id is 36731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237770906-C-T is described in Lovd as [Benign]. Variant chr1-237770906-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.019 (2889/152272) while in subpopulation NFE AF= 0.0292 (1986/68026). AF 95% confidence interval is 0.0281. There are 46 homozygotes in gnomad4. There are 1459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2889 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11557+19C>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.11557+19C>T		intron_variant		1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000659194.3	c.11545+19C>T		intron_variant				ENSP00000499653
RYR2	ENST00000660292.2	c.11578+19C>T		intron_variant				ENSP00000499787
RYR2	ENST00000609119.2	c.*2649+19C>T		intron_variant, NMD_transcript_variant		5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2891 AN: 152154 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0178 AC: 2709 AN: 151872 Hom.: 48 AF XY: 0.0173 AC XY: 1386 AN XY: 80286

Gnomad AFR exome AF: 0.00415

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00169

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0262 AC: 34667 AN: 1323002 Hom.: 574 Cov.: 20 AF XY: 0.0254 AC XY: 16643 AN XY: 654568

Gnomad4 AFR exome AF: 0.00375

Gnomad4 AMR exome AF: 0.00633

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.0417

Gnomad4 NFE exome AF: 0.0306

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0190 AC: 2889 AN: 152272 Hom.: 46 Cov.: 32 AF XY: 0.0196 AC XY: 1459 AN XY: 74454

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0427

Gnomad4 NFE AF: 0.0292

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0200 Hom.: 13

Bravo AF: 0.0164

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2018	Variant summary: The RYR2 c.11557+19C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3274/177350 control chromosomes (53 homozygotes) at a frequency of 0.0184607, which is approximately 336 times the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
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	Eurofins Ntd Llc (ga)	Sep 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, Academic Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.080
DANN	Benign	0.29

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs113408406; hg19: chr1-237934206;