rs12116442

Positions:

• chr1-237608276-G-A
• chr1-237608276-G-T

Variant summary

Our verdict is Benign. Variant got -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

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.4684-2486G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.4684-2486G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.4684-2486G>A		intron_variant
RYR2	ENST00000660292.2	c.4684-2486G>A		intron_variant
RYR2	ENST00000609119.2	c.4684-2486G>A		intron_variant, NMD_transcript_variant		5

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

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.188

Alfa AF: 0.193 Hom.: 3724

Bravo AF: 0.193

Asia WGS AF: 0.316 AC: 1099 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	4.2
DANN	Benign	0.76

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: rs12116442; hg19: chr1-237771576;