1-237445542-C-T

Position:

• chr1-237445542-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.1292+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,611,854 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (96 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.376

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]

RYR2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-237445542-C-T is Benign according to our data. Variant chr1-237445542-C-T is described in ClinVar as [Benign]. Clinvar id is 138938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237445542-C-T is described in Lovd as [Benign]. Variant chr1-237445542-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00565 (859/152128) while in subpopulation SAS AF= 0.0258 (124/4808). AF 95% confidence interval is 0.0221. There are 9 homozygotes in gnomad4. There are 430 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 859 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1292+20C>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.1292+20C>T		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1292+20C>T		intron_variant		5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1292+20C>T		intron_variant				ENSP00000499787.2
RYR2	ENST00000659194.3	c.1292+20C>T		intron_variant				ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 863 AN: 152010 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00768

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00810 AC: 2011 AN: 248384 Hom.: 31 AF XY: 0.00933 AC XY: 1258 AN XY: 134764

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0265

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00825

Gnomad OTH exome AF: 0.00947

GnomAD4 exome AF: 0.00775 AC: 11307 AN: 1459726 Hom.: 96 Cov.: 30 AF XY: 0.00850 AC XY: 6171 AN XY: 726214

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00377

Gnomad4 ASJ exome AF: 0.00460

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00711

Gnomad4 OTH exome AF: 0.00817

GnomAD4 genome AF: 0.00565 AC: 859 AN: 152128 Hom.: 9 Cov.: 32 AF XY: 0.00578 AC XY: 430 AN XY: 74368

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00727

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0258

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00768

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00722 Hom.: 2

Bravo AF: 0.00517

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2019	Variant summary: RYR2 c.1292+20C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0081 in 248384 control chromosomes in the gnomAD database, including 31 homozygotes. The observed variant frequency is approximately 324 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1292+20C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2011	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. -

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.17
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs182050281; hg19: chr1-237608842;