rs34967813

Variant names:

• chr1-237678090-A-G
• rs34967813
• NM_001035.3:c.8873A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.8873A>G​(p.Gln2958Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,596,616 control chromosomes in the GnomAD database, including 62,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2958K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (4190 hom., cov: 33)
  • Exomes 𝑓: 0.27 (58769 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 7.21
• Publications: 39 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: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -19 ACMG points.

• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015868247).
• BP6: Variant 1-237678090-A-G is Benign according to our data. Variant chr1-237678090-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.8873A>G	p.Gln2958Arg	missense	Exon 61 of 105	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.8873A>G	p.Gln2958Arg	missense	Exon 61 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.8873A>G	p.Gln2958Arg	missense	Exon 61 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.8831-2366A>G		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30640 AN: 152112 Hom.: 4190 Cov.: 33

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.214 AC: 51651 AN: 241208 AF XY: 0.214

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.000736

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.243

GnomAD4 exome AF: 0.271 AC: 391396 AN: 1444386 Hom.: 58769 Cov.: 27 AF XY: 0.267 AC XY: 191525 AN XY: 718562

African (AFR) AF: 0.0417 AC: 1388 AN: 33306

American (AMR) AF: 0.199 AC: 8733 AN: 43922

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5716 AN: 25884

East Asian (EAS) AF: 0.000556 AC: 22 AN: 39588

South Asian (SAS) AF: 0.0804 AC: 6838 AN: 85088

European-Finnish (FIN) AF: 0.246 AC: 13078 AN: 53062

Middle Eastern (MID) AF: 0.180 AC: 1031 AN: 5728

European-Non Finnish (NFE) AF: 0.310 AC: 340654 AN: 1097996

Other (OTH) AF: 0.233 AC: 13936 AN: 59812

GnomAD4 genome AF: 0.201 AC: 30630 AN: 152230 Hom.: 4190 Cov.: 33 AF XY: 0.194 AC XY: 14448 AN XY: 74436

African (AFR) AF: 0.0536 AC: 2227 AN: 41568

American (AMR) AF: 0.213 AC: 3252 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 736 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0767 AC: 370 AN: 4824

European-Finnish (FIN) AF: 0.230 AC: 2440 AN: 10602

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21037 AN: 67974

Other (OTH) AF: 0.184 AC: 389 AN: 2114

Alfa AF: 0.270 Hom.: 23405

Bravo AF: 0.194

TwinsUK AF: 0.311 AC: 1152

ALSPAC AF: 0.319 AC: 1230

ESP6500AA AF: 0.0526 AC: 199

ESP6500EA AF: 0.304 AC: 2499

ExAC AF: 0.211 AC: 25492

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.41
Sift	Benign	0.47	T
Polyphen		0.29	B
Vest4		0.36
MPC		0.50
ClinPred		0.050	T
GERP RS		5.7
Varity_R		0.34
gMVP		0.57
Mutation Taster		=74/26	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34967813; hg19: chr1-237841390; COSMIC: COSV63683862;