chr1-237454578-C-T

Position:

• chr1-237454578-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001035.3(RYR2):​c.1476+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,611,920 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.001445
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 0.112

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-237454578-C-T is Benign according to our data. Variant chr1-237454578-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43747.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr1-237454578-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1476+4C>T		splice_region_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.1476+4C>T		splice_region_variant, intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.1476+4C>T		splice_region_variant, intron_variant		5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.1476+4C>T		splice_region_variant, intron_variant				ENSP00000499787.2
RYR2	ENST00000659194.3	c.1476+4C>T		splice_region_variant, intron_variant				ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000158 AC: 39 AN: 246228 Hom.: 0 AF XY: 0.000180 AC XY: 24 AN XY: 133578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1459786 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 157 AN XY: 726142

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000147

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RYR2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2013	The 1476+4C>T variant in RYR2 has been identified by our laboratory in one Cauca sian individual with HCM (LMM unpublished data) and in 1/8208 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/). This may represent a presymptomatic individual. This variant is located i n the 5' splice region. Computational tools do not suggest an impact to splicing . However, this information is not predictive enough to rule out pathogenicity. Additional studies are needed to fully assess its clinical significance. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2022	Variant summary: RYR2 c.1476+4C>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 0.00016 in 246228 control chromosomes. The observed variant frequency is approximately 4.61 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.1476+4C>T has been reported in the literature in individuals affected with HCM in a patient who also carried a MYBPC3 variant that could explain the disease in the patient (Mademont-Soler_2017). This report does not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2023	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change falls in intron 15 of the RYR2 gene. It does not directly change the encoded amino acid sequence of the RYR2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369442980, gnomAD 0.06%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 43747). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2024

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.090
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: rs369442980; hg19: chr1-237617878;