rs2805396

Variant names:

• chr1-237569095-G-A
• rs2805396
• NM_001035.3:c.3424-50G>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.3424-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,551,862 control chromosomes in the GnomAD database, including 363,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28394 hom., cov: 30)
  • Exomes 𝑓: 0.69 (335014 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.329
• Publications: 6 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-237569095-G-A is Benign according to our data. Variant chr1-237569095-G-A is described in ClinVar as Benign. ClinVar VariationId is 257208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 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.3424-50G>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.3424-50G>A		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.3424-50G>A		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.3424-50G>A		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88360 AN: 151684 Hom.: 28378 Cov.: 30

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.628

Gnomad NFE AF: 0.710

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.648 AC: 139415 AN: 215306 AF XY: 0.656

Gnomad AFR exome AF: 0.307

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.264

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.713

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.685 AC: 959238 AN: 1400060 Hom.: 335014 Cov.: 23 AF XY: 0.687 AC XY: 474151 AN XY: 689832

African (AFR) AF: 0.308 AC: 9906 AN: 32186

American (AMR) AF: 0.738 AC: 29204 AN: 39566

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 18129 AN: 23330

East Asian (EAS) AF: 0.297 AC: 11492 AN: 38758

South Asian (SAS) AF: 0.685 AC: 53162 AN: 77642

European-Finnish (FIN) AF: 0.670 AC: 34402 AN: 51332

Middle Eastern (MID) AF: 0.688 AC: 3263 AN: 4744

European-Non Finnish (NFE) AF: 0.709 AC: 761850 AN: 1074930

Other (OTH) AF: 0.657 AC: 37830 AN: 57572

GnomAD4 genome AF: 0.582 AC: 88408 AN: 151802 Hom.: 28394 Cov.: 30 AF XY: 0.581 AC XY: 43086 AN XY: 74174

African (AFR) AF: 0.318 AC: 13147 AN: 41376

American (AMR) AF: 0.692 AC: 10573 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 2695 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1413 AN: 5140

South Asian (SAS) AF: 0.667 AC: 3203 AN: 4800

European-Finnish (FIN) AF: 0.656 AC: 6898 AN: 10512

Middle Eastern (MID) AF: 0.624 AC: 181 AN: 290

European-Non Finnish (NFE) AF: 0.710 AC: 48246 AN: 67922

Other (OTH) AF: 0.610 AC: 1287 AN: 2110

Alfa AF: 0.663 Hom.: 6481

Bravo AF: 0.573

Asia WGS AF: 0.474 AC: 1650 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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.27
DANN	Benign	0.79
PhyloP100		-0.33
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: rs2805396; hg19: chr1-237732395; COSMIC: COSV63673625;