rs199562036

Variant names:

• chr1-237778782-AACTG-A
• rs199562036
• NM_001035.3:c.11880+13_11880+16delACTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.11880+13_11880+16delACTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,401,478 control chromosomes in the GnomAD database, including 188 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.014 (170 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0560
• 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 -16 ACMG points.

• BP6: Variant 1-237778782-AACTG-A is Benign according to our data. Variant chr1-237778782-AACTG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 177974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0106 (1619/152328) while in subpopulation SAS AF = 0.0157 (76/4830). AF 95% confidence interval is 0.0144. There are 18 homozygotes in GnomAd4. There are 750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1619 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.11880+13_11880+16delACTG		intron	N/A	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.11880+13_11880+16delACTG		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11904+13_11904+16delACTG		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2972+13_*2972+16delACTG		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1621 AN: 152210 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0111 AC: 2752 AN: 248142 AF XY: 0.0119

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00836

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0140 AC: 17543 AN: 1249150 Hom.: 170 AF XY: 0.0141 AC XY: 8942 AN XY: 632182

African (AFR) AF: 0.00247 AC: 72 AN: 29168

American (AMR) AF: 0.00833 AC: 370 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00368 AC: 91 AN: 24740

East Asian (EAS) AF: 0.0000517 AC: 2 AN: 38692

South Asian (SAS) AF: 0.0165 AC: 1350 AN: 82018

European-Finnish (FIN) AF: 0.00353 AC: 188 AN: 53254

Middle Eastern (MID) AF: 0.0232 AC: 125 AN: 5380

European-Non Finnish (NFE) AF: 0.0160 AC: 14699 AN: 918142

Other (OTH) AF: 0.0121 AC: 646 AN: 53318

GnomAD4 genome AF: 0.0106 AC: 1619 AN: 152328 Hom.: 18 Cov.: 32 AF XY: 0.0101 AC XY: 750 AN XY: 74488

African (AFR) AF: 0.00305 AC: 127 AN: 41580

American (AMR) AF: 0.0157 AC: 240 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4830

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1034 AN: 68034

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0106 Hom.: 0

Bravo AF: 0.0107

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.056
Mutation Taster		=100/0	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: rs199562036; hg19: chr1-237942082; COSMIC: COSV105920987;