rs10925490

Variant names:

• chr1-237664346-A-G
• rs10925490
• NM_001035.3:c.8437-2166A>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.8437-2166A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 152,250 control chromosomes in the GnomAD database, including 542 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 0.067 (542 hom., cov: 33)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.173 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.8437-2166A>G		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.8437-2166A>G		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.8437-2166A>G		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.8437-2166A>G		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10145 AN: 152132 Hom.: 537 Cov.: 33

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.0707

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0635

Gnomad OTH AF: 0.0555

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

GnomAD4 genome AF: 0.0667 AC: 10155 AN: 152250 Hom.: 542 Cov.: 33 AF XY: 0.0700 AC XY: 5215 AN XY: 74452

African (AFR) AF: 0.0301 AC: 1252 AN: 41570

American (AMR) AF: 0.178 AC: 2725 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.0703 AC: 363 AN: 5166

South Asian (SAS) AF: 0.116 AC: 559 AN: 4818

European-Finnish (FIN) AF: 0.0590 AC: 626 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0635 AC: 4318 AN: 68002

Other (OTH) AF: 0.0540 AC: 114 AN: 2112

Alfa AF: 0.0683 Hom.: 410

Bravo AF: 0.0724

Asia WGS AF: 0.0930 AC: 324 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.76
PhyloP100		-0.23
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: rs10925490; hg19: chr1-237827646;