rs3753617

Variant names:

• chr1-237461483-A-C
• rs3753617
• NM_001035.3:c.1612+4748A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-237461483-A-C
• chr1-237461483-A-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.1612+4748A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 151,366 control chromosomes in the GnomAD database, including 22,687 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 0.53 (22687 hom., cov: 30)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95
• Publications: 2 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=-1.06).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 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.1612+4748A>C		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.1612+4748A>C		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.1612+4748A>C		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.1612+4748A>C		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80497 AN: 151248 Hom.: 22681 Cov.: 30

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.532 AC: 80533 AN: 151366 Hom.: 22687 Cov.: 30 AF XY: 0.536 AC XY: 39659 AN XY: 73978

African (AFR) AF: 0.342 AC: 14078 AN: 41134

American (AMR) AF: 0.566 AC: 8613 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2029 AN: 3460

East Asian (EAS) AF: 0.803 AC: 4122 AN: 5134

South Asian (SAS) AF: 0.573 AC: 2745 AN: 4790

European-Finnish (FIN) AF: 0.602 AC: 6320 AN: 10498

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.602 AC: 40800 AN: 67830

Other (OTH) AF: 0.531 AC: 1111 AN: 2094

Alfa AF: 0.564 Hom.: 11568

Bravo AF: 0.517

Asia WGS AF: 0.653 AC: 2271 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.049
DANN	Benign	0.22
PhyloP100		-1.9
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: rs3753617; hg19: chr1-237624783;