rs2819757

Positions:

• chr1-237715647-A-G
• chr1-237715647-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001035.3(RYR2):​c.10324-1551A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,978 control chromosomes in the GnomAD database, including 24,784 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 (24784 hom., cov: 32)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.836

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.10324-1551A>G		intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.10324-1551A>G		intron_variant		1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.1	c.130-1551A>G		intron_variant				ENSP00000499393.2
RYR2	ENST00000609119.2	n.*1359-1551A>G		intron_variant		5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79845 AN: 151860 Hom.: 24792 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.525 AC: 79828 AN: 151978 Hom.: 24784 Cov.: 32 AF XY: 0.527 AC XY: 39181 AN XY: 74280

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.710

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.635

Gnomad4 FIN AF: 0.717

Gnomad4 NFE AF: 0.695

Gnomad4 OTH AF: 0.549

Alfa AF: 0.647 Hom.: 13637

Bravo AF: 0.497

Asia WGS AF: 0.497 AC: 1712 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs2819757; hg19: chr1-237878947;