rs2249287

Variant names:

• chr1-237774574-C-T
• rs2249287
• NM_001035.3:c.11775+926C>T

Variant summary

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

The NM_001035.3(RYR2):​c.11775+926C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,016 control chromosomes in the GnomAD database, including 3,329 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 (3329 hom., cov: 32)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.850
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.11775+926C>T		intron_variant	Intron 87 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.11775+926C>T		intron_variant	Intron 87 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.11799+926C>T		intron_variant	Intron 88 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*2867+926C>T		intron_variant	Intron 86 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31015 AN: 151898 Hom.: 3325 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.0292

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.204 AC: 31038 AN: 152016 Hom.: 3329 Cov.: 32 AF XY: 0.198 AC XY: 14742 AN XY: 74324

African (AFR) AF: 0.270 AC: 11195 AN: 41438

American (AMR) AF: 0.153 AC: 2334 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 626 AN: 3470

East Asian (EAS) AF: 0.0293 AC: 151 AN: 5156

South Asian (SAS) AF: 0.179 AC: 862 AN: 4818

European-Finnish (FIN) AF: 0.155 AC: 1640 AN: 10588

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13648 AN: 67964

Other (OTH) AF: 0.197 AC: 415 AN: 2104

Alfa AF: 0.199 Hom.: 1430

Bravo AF: 0.206

Asia WGS AF: 0.102 AC: 354 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.64
PhyloP100		-0.85
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: rs2249287; hg19: chr1-237937874;