rs114289907

Variant names:

• chr1-237792064-A-G
• rs114289907
• NM_001035.3:c.13564-41A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.13564-41A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,414,876 control chromosomes in the GnomAD database, including 1,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (135 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1254 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.256
• Publications: 4 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

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-237792064-A-G is Benign according to our data. Variant chr1-237792064-A-G is described in ClinVar as Benign. ClinVar VariationId is 218487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 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.13564-41A>G		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.13564-41A>G		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.13582-41A>G		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*4656-41A>G		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6171 AN: 152006 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0330

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0526

GnomAD2 exomes AF: 0.0436 AC: 7058 AN: 161706 AF XY: 0.0480

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0352

Gnomad EAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0364 AC: 45985 AN: 1262752 Hom.: 1254 Cov.: 18 AF XY: 0.0389 AC XY: 24544 AN XY: 630476

African (AFR) AF: 0.0575 AC: 1663 AN: 28930

American (AMR) AF: 0.0269 AC: 960 AN: 35628

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 863 AN: 24186

East Asian (EAS) AF: 0.0214 AC: 760 AN: 35442

South Asian (SAS) AF: 0.110 AC: 8438 AN: 76768

European-Finnish (FIN) AF: 0.0234 AC: 1139 AN: 48704

Middle Eastern (MID) AF: 0.105 AC: 568 AN: 5388

European-Non Finnish (NFE) AF: 0.0307 AC: 29320 AN: 954108

Other (OTH) AF: 0.0424 AC: 2274 AN: 53598

GnomAD4 genome AF: 0.0406 AC: 6175 AN: 152124 Hom.: 135 Cov.: 32 AF XY: 0.0413 AC XY: 3072 AN XY: 74360

African (AFR) AF: 0.0544 AC: 2258 AN: 41482

American (AMR) AF: 0.0329 AC: 503 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.0340 AC: 175 AN: 5152

South Asian (SAS) AF: 0.114 AC: 545 AN: 4798

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10612

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0322 AC: 2193 AN: 68014

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0349 Hom.: 167

Bravo AF: 0.0415

Asia WGS AF: 0.0660 AC: 228 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.80
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs114289907; hg19: chr1-237955364; COSMIC: COSV63707450;