rs188671846

Variant names:

• chr1-237705210-T-C
• rs188671846
• NM_001035.3:c.9450-3T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):​c.9450-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,606,270 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001941
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.270
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-237705210-T-C is Benign according to our data. Variant chr1-237705210-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43838.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000473 (72/152302) while in subpopulation AMR AF = 0.00379 (58/15296). AF 95% confidence interval is 0.00301. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.9450-3T>C		splice_region intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.9450-3T>C		splice_region intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.9450-3T>C		splice_region intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*485-3T>C		splice_region intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000395 AC: 94 AN: 237708 AF XY: 0.000351

Gnomad AFR exome AF: 0.0000681

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.000281 AC: 408 AN: 1453968 Hom.: 0 Cov.: 30 AF XY: 0.000269 AC XY: 194 AN XY: 722316

African (AFR) AF: 0.0000598 AC: 2 AN: 33424

American (AMR) AF: 0.00189 AC: 83 AN: 43900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 84784

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000270 AC: 299 AN: 1107408

Other (OTH) AF: 0.000366 AC: 22 AN: 60098

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00379 AC: 58 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000635

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Jan 22, 2024

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.9450-3T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 0.0003 in 1606270 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 12-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, c.9450-3T>C has not been reported in the literature in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28404607). ClinVar contains an entry for this variant (Variation ID: 43838). Based on the evidence outlined above, the variant was classified as benign.

Mar 09, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 9450-3T>C variant in RYR2 has not been reported in the literature but has be en previously identified in one Caucasian individual with DCM by our laboratory. This variant has been identified in 1/28 Iberian chromosomes from a broad popul ation by the 1000 Genomes project (dbSNP rs188671846), though this may be a pres ymptomatic individual. In addition, this variant is located in the 3' splice reg ion but computational tools do not suggest an impact to splicing. Additional inf ormation is needed to fully assess the clinical significance of this variant.

not provided Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiomyopathy Benign:1

Oct 25, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Nov 24, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.046
DANN	Benign	0.63
PhyloP100		-0.27
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0080
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

Other links and lift over

dbSNP: rs188671846; hg19: chr1-237868510;