rs4427395

Variant names:

• chr1-237699287-G-A
• rs4427395
• NM_001035.3:c.9128+262G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001035.3(RYR2):​c.9128+262G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 151,962 control chromosomes in the GnomAD database, including 25,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (25669 hom., cov: 32)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.186
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-237699287-G-A is Benign according to our data. Variant chr1-237699287-G-A is described in ClinVar as Benign. ClinVar VariationId is 683792.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.9128+262G>A		intron_variant	Intron 64 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.9128+262G>A		intron_variant	Intron 64 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.9128+262G>A		intron_variant	Intron 64 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*163+262G>A		intron_variant	Intron 62 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81489 AN: 151846 Hom.: 25677 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.566

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81475 AN: 151962 Hom.: 25669 Cov.: 32 AF XY: 0.539 AC XY: 40057 AN XY: 74268

African (AFR) AF: 0.193 AC: 8003 AN: 41474

American (AMR) AF: 0.605 AC: 9240 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2251 AN: 3468

East Asian (EAS) AF: 0.391 AC: 2014 AN: 5150

South Asian (SAS) AF: 0.651 AC: 3135 AN: 4814

European-Finnish (FIN) AF: 0.686 AC: 7232 AN: 10548

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.701 AC: 47644 AN: 67932

Other (OTH) AF: 0.567 AC: 1196 AN: 2110

Alfa AF: 0.644 Hom.: 118338

Bravo AF: 0.511

Asia WGS AF: 0.519 AC: 1802 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4427395; hg19: chr1-237862587;