chr1-237377315-A-C

Position:

• chr1-237377315-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.464-8A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,595,424 control chromosomes in the GnomAD database, including 59,200 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9495 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49705 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002350
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.49

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=-0.89).
• BP6: Variant 1-237377315-A-C is Benign according to our data. Variant chr1-237377315-A-C is described in ClinVar as [Benign]. Clinvar id is 43790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237377315-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.464-8A>C		splice_region_variant, 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.464-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	ENSP00000355533	P1
RYR2	ENST00000659194.3	c.464-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499653
RYR2	ENST00000660292.2	c.464-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499787
RYR2	ENST00000609119.2	c.464-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000499659

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50500 AN: 151912 Hom.: 9467 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.316

GnomAD3 exomes AF: 0.290 AC: 69503 AN: 239434 Hom.: 11094 AF XY: 0.279 AC XY: 36274 AN XY: 129884

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.435

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.253 AC: 365205 AN: 1443394 Hom.: 49705 Cov.: 28 AF XY: 0.251 AC XY: 179856 AN XY: 717104

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.344

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.479

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.333 AC: 50567 AN: 152030 Hom.: 9495 Cov.: 32 AF XY: 0.336 AC XY: 24998 AN XY: 74298

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.311

Alfa AF: 0.246 Hom.: 9453

Bravo AF: 0.341

Asia WGS AF: 0.325 AC: 1128 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 01, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2014	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:3

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Arrhythmogenic right ventricular dysplasia 2 Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 09, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

This alteration is classified as 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. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0020
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: rs10925391; hg19: chr1-237540615; COSMIC: COSV63672220;