rs9428384

Variant names:

• chr1-237801831-G-A
• rs9428384
• NM_001035.3:c.14091-25G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-237801831-G-A
• chr1-237801831-G-C
• chr1-237801831-G-T

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.14091-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,447,184 control chromosomes in the GnomAD database, including 121,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10781 hom., cov: 31)
  • Exomes 𝑓: 0.41 (111009 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0840
• 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=-0.96).
• BP6: Variant 1-237801831-G-A is Benign according to our data. Variant chr1-237801831-G-A is described in ClinVar as Benign. ClinVar VariationId is 257203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 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.14091-25G>A		intron	N/A	NP_001026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.14091-25G>A		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.14109-25G>A		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*5183-25G>A		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.367 AC: 54808 AN: 149540 Hom.: 10778 Cov.: 31

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.389

GnomAD2 exomes AF: 0.413 AC: 93115 AN: 225654 AF XY: 0.418

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.407 AC: 527615 AN: 1297538 Hom.: 111009 Cov.: 19 AF XY: 0.410 AC XY: 265680 AN XY: 648240

African (AFR) AF: 0.208 AC: 6356 AN: 30524

American (AMR) AF: 0.357 AC: 15103 AN: 42274

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 11957 AN: 24198

East Asian (EAS) AF: 0.643 AC: 24744 AN: 38460

South Asian (SAS) AF: 0.477 AC: 37236 AN: 78062

European-Finnish (FIN) AF: 0.398 AC: 17372 AN: 43608

Middle Eastern (MID) AF: 0.487 AC: 2585 AN: 5306

European-Non Finnish (NFE) AF: 0.397 AC: 389595 AN: 980772

Other (OTH) AF: 0.417 AC: 22667 AN: 54334

GnomAD4 genome AF: 0.366 AC: 54823 AN: 149646 Hom.: 10781 Cov.: 31 AF XY: 0.368 AC XY: 26930 AN XY: 73082

African (AFR) AF: 0.231 AC: 9166 AN: 39738

American (AMR) AF: 0.348 AC: 5279 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1673 AN: 3466

East Asian (EAS) AF: 0.641 AC: 3270 AN: 5100

South Asian (SAS) AF: 0.491 AC: 2354 AN: 4790

European-Finnish (FIN) AF: 0.406 AC: 4183 AN: 10308

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27604 AN: 67766

Other (OTH) AF: 0.390 AC: 815 AN: 2090

Alfa AF: 0.386 Hom.: 1749

Bravo AF: 0.354

Asia WGS AF: 0.495 AC: 1711 AN: 3452

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	-0.96
CADD	Benign	4.4
DANN	Benign	0.48
PhyloP100		-0.084
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: rs9428384; hg19: chr1-237965131;