1-237281799-T-C

Variant names:

• chr1-237281799-T-C
• rs12046077
• NM_001035.3:c.168+11183T>C

Variant summary

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

The NM_001035.3(RYR2):​c.168+11183T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,068 control chromosomes in the GnomAD database, including 7,422 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 0.30 (7422 hom., cov: 33)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 5 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 = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.168+11183T>C		intron_variant	Intron 2 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.168+11183T>C		intron_variant	Intron 2 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.168+11183T>C		intron_variant	Intron 2 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.168+11183T>C		intron_variant	Intron 2 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45517 AN: 151950 Hom.: 7415 Cov.: 33

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.299 AC: 45541 AN: 152068 Hom.: 7422 Cov.: 33 AF XY: 0.307 AC XY: 22802 AN XY: 74346

African (AFR) AF: 0.240 AC: 9972 AN: 41498

American (AMR) AF: 0.293 AC: 4475 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1134 AN: 3472

East Asian (EAS) AF: 0.719 AC: 3710 AN: 5160

South Asian (SAS) AF: 0.360 AC: 1735 AN: 4816

European-Finnish (FIN) AF: 0.378 AC: 3991 AN: 10568

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19524 AN: 67970

Other (OTH) AF: 0.317 AC: 668 AN: 2106

Alfa AF: 0.272 Hom.: 3506

Bravo AF: 0.293

Asia WGS AF: 0.539 AC: 1871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.070
DANN	Benign	0.79
PhyloP100		-1.1
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: rs12046077; hg19: chr1-237445099; COSMIC: COSV63672858;