1-237598193-A-G

Variant names:

• chr1-237598193-A-G
• rs1074189
• NM_001035.3:c.4596+2536A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001035.3(RYR2):​c.4596+2536A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 152,108 control chromosomes in the GnomAD database, including 6,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6723 hom., cov: 32)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.319
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

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.4596+2536A>G		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.4596+2536A>G		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.4596+2536A>G		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.4596+2536A>G		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43637 AN: 151990 Hom.: 6725 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.274

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

GnomAD4 genome AF: 0.287 AC: 43656 AN: 152108 Hom.: 6723 Cov.: 32 AF XY: 0.291 AC XY: 21628 AN XY: 74370

African (AFR) AF: 0.314 AC: 13013 AN: 41478

American (AMR) AF: 0.234 AC: 3574 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3468

East Asian (EAS) AF: 0.603 AC: 3108 AN: 5154

South Asian (SAS) AF: 0.291 AC: 1404 AN: 4824

European-Finnish (FIN) AF: 0.326 AC: 3447 AN: 10582

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.259 AC: 17639 AN: 67990

Other (OTH) AF: 0.274 AC: 579 AN: 2112

Alfa AF: 0.284 Hom.: 1902

Bravo AF: 0.282

Asia WGS AF: 0.422 AC: 1466 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.8
DANN	Benign	0.52
PhyloP100		0.32
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: rs1074189; hg19: chr1-237761493;