rs186181155

Variant names:

• chr1-237511729-G-A
• rs186181155
• NM_001035.3:c.2760G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001035.3(RYR2):​c.2760G>A​(p.Glu920Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,570,506 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: RYR2 NM_001035.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: -0.0190
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-237511729-G-A is Benign according to our data. Variant chr1-237511729-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43762.
• BP7: Synonymous conserved (PhyloP=-0.019 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (300/150222) while in subpopulation NFE AF = 0.0034 (230/67600). AF 95% confidence interval is 0.00304. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 300 AD gene.

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.2760G>A	p.Glu920Glu	synonymous	Exon 24 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.2760G>A	p.Glu920Glu	synonymous	Exon 24 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.2760G>A	p.Glu920Glu	synonymous	Exon 24 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.2760G>A		non_coding_transcript_exon	Exon 24 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 300 AN: 150090 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000779

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00175

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00155 AC: 312 AN: 200734 AF XY: 0.00156

Gnomad AFR exome AF: 0.000664

Gnomad AMR exome AF: 0.000889

Gnomad ASJ exome AF: 0.000659

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000632

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00254 AC: 3610 AN: 1420284 Hom.: 5 Cov.: 31 AF XY: 0.00242 AC XY: 1698 AN XY: 703004

African (AFR) AF: 0.000640 AC: 21 AN: 32838

American (AMR) AF: 0.000906 AC: 36 AN: 39752

Ashkenazi Jewish (ASJ) AF: 0.000834 AC: 21 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 38182

South Asian (SAS) AF: 0.00 AC: 0 AN: 80870

European-Finnish (FIN) AF: 0.000669 AC: 34 AN: 50834

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5700

European-Non Finnish (NFE) AF: 0.00310 AC: 3379 AN: 1088276

Other (OTH) AF: 0.00199 AC: 117 AN: 58662

GnomAD4 genome AF: 0.00200 AC: 300 AN: 150222 Hom.: 1 Cov.: 29 AF XY: 0.00184 AC XY: 135 AN XY: 73174

African (AFR) AF: 0.000777 AC: 32 AN: 41190

American (AMR) AF: 0.00175 AC: 26 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4988

South Asian (SAS) AF: 0.00 AC: 0 AN: 4726

European-Finnish (FIN) AF: 0.000198 AC: 2 AN: 10096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00340 AC: 230 AN: 67600

Other (OTH) AF: 0.00191 AC: 4 AN: 2090

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	5	not specified (5)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (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
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.8
DANN	Benign	0.59
PhyloP100		-0.019
Mutation Taster		=99/1	polymorphism

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: rs186181155; hg19: chr1-237675029; COSMIC: COSV63701544;