NM_001035.3:c.13476+47G>A

Variant names:

• chr1-237788182-G-A
• rs16835818
• NM_001035.3:c.13476+47G>A

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.13476+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,449,050 control chromosomes in the GnomAD database, including 66,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9830 hom., cov: 32)
  • Exomes 𝑓: 0.29 (56197 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.598
• Publications: 8 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

ENSG00000296715 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-237788182-G-A is Benign according to our data. Variant chr1-237788182-G-A is described in ClinVar as Benign. ClinVar VariationId is 257200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 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.13476+47G>A		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.13476+47G>A		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.13494+47G>A		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*4568+47G>A		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51381 AN: 151976 Hom.: 9808 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.267 AC: 49709 AN: 185982 AF XY: 0.269

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.288 AC: 373606 AN: 1296954 Hom.: 56197 Cov.: 17 AF XY: 0.287 AC XY: 183848 AN XY: 641316

African (AFR) AF: 0.528 AC: 15311 AN: 29020

American (AMR) AF: 0.162 AC: 5679 AN: 34960

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 5511 AN: 22340

East Asian (EAS) AF: 0.101 AC: 3794 AN: 37668

South Asian (SAS) AF: 0.234 AC: 16431 AN: 70320

European-Finnish (FIN) AF: 0.256 AC: 12920 AN: 50480

Middle Eastern (MID) AF: 0.276 AC: 1451 AN: 5260

European-Non Finnish (NFE) AF: 0.299 AC: 296846 AN: 993038

Other (OTH) AF: 0.291 AC: 15663 AN: 53868

GnomAD4 genome AF: 0.338 AC: 51439 AN: 152096 Hom.: 9830 Cov.: 32 AF XY: 0.331 AC XY: 24626 AN XY: 74368

African (AFR) AF: 0.519 AC: 21519 AN: 41458

American (AMR) AF: 0.244 AC: 3727 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 825 AN: 3470

East Asian (EAS) AF: 0.109 AC: 565 AN: 5190

South Asian (SAS) AF: 0.228 AC: 1098 AN: 4820

European-Finnish (FIN) AF: 0.256 AC: 2713 AN: 10578

Middle Eastern (MID) AF: 0.305 AC: 89 AN: 292

European-Non Finnish (NFE) AF: 0.296 AC: 20103 AN: 67996

Other (OTH) AF: 0.307 AC: 649 AN: 2114

Alfa AF: 0.310 Hom.: 10785

Bravo AF: 0.345

Asia WGS AF: 0.184 AC: 641 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.68
PhyloP100		-0.60
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: rs16835818; hg19: chr1-237951482; COSMIC: COSV63708316; COSMIC: COSV63708316;