rs370972311

Positions:

• chr1-237634877-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000366574.7(RYR2):​c.6689-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,589,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: RYR2 ENST00000366574.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01522
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.308

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-237634877-T-C is Benign according to our data. Variant chr1-237634877-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165104.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=4}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000272 (391/1437480) while in subpopulation MID AF= 0.0113 (65/5748). AF 95% confidence interval is 0.0091. There are 1 homozygotes in gnomad4_exome. There are 203 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.6689-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.6689-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000659194.3	c.6689-12T>C		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499653
RYR2	ENST00000660292.2	c.6689-12T>C		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499787
RYR2	ENST00000609119.2	c.6689-12T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000304 AC: 67 AN: 220092 Hom.: 1 AF XY: 0.000331 AC XY: 39 AN XY: 117886

Gnomad AFR exome AF: 0.0000746

Gnomad AMR exome AF: 0.0000963

Gnomad ASJ exome AF: 0.000531

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000415

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000419

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.000272 AC: 391 AN: 1437480 Hom.: 1 Cov.: 29 AF XY: 0.000285 AC XY: 203 AN XY: 713072

Gnomad4 AFR exome AF: 0.000302

Gnomad4 AMR exome AF: 0.000144

Gnomad4 ASJ exome AF: 0.000195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000328

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.000436

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74492

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000395 Hom.: 1

Bravo AF: 0.000261

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2019	Variant summary: RYR2 c.6689-12T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.0003 in 220092 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.6689-12T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cite the variant twice as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2015	c.6689-12T>C in intron 43 of RYR2: This variant is not expected to have clinical significance because a T>C change at this position does not diverge from the sp lice consensus sequence and is therefore unlikely to impact splicing. It has bee n identified in 0.1% (22/21894) of European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370972311). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2014	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. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 16, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

RYR2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.11		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: rs370972311; hg19: chr1-237798177;