chr1-237608276-G-A

Variant names:

• chr1-237608276-G-A
• rs12116442
• NM_001035.3:c.4684-2486G>A

Variant summary

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

The NM_001035.3(RYR2):​c.4684-2486G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,132 control chromosomes in the GnomAD database, including 3,472 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 0.20 (3472 hom., cov: 32)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 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.4684-2486G>A		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.4684-2486G>A		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.4684-2486G>A		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.4684-2486G>A		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30834 AN: 152014 Hom.: 3476 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.203 AC: 30838 AN: 152132 Hom.: 3472 Cov.: 32 AF XY: 0.208 AC XY: 15434 AN XY: 74368

African (AFR) AF: 0.156 AC: 6485 AN: 41534

American (AMR) AF: 0.177 AC: 2702 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 568 AN: 3470

East Asian (EAS) AF: 0.468 AC: 2403 AN: 5136

South Asian (SAS) AF: 0.259 AC: 1247 AN: 4820

European-Finnish (FIN) AF: 0.274 AC: 2894 AN: 10572

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.206 AC: 13989 AN: 67994

Other (OTH) AF: 0.188 AC: 398 AN: 2116

Alfa AF: 0.193 Hom.: 4771

Bravo AF: 0.193

Asia WGS AF: 0.316 AC: 1099 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.2
DANN	Benign	0.76
PhyloP100		0.029
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: rs12116442; hg19: chr1-237771576;