rs1332777

Variant names:

• chr1-237591040-A-G
• rs1332777
• NM_001035.3:c.4160+48A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-237591040-A-G
• chr1-237591040-A-C

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.4160+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,388,112 control chromosomes in the GnomAD database, including 157,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12981 hom., cov: 28)
  • Exomes 𝑓: 0.46 (144603 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0570
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-237591040-A-G is Benign according to our data. Variant chr1-237591040-A-G is described in ClinVar as Benign. ClinVar VariationId is 257210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.487 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.4160+48A>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.4160+48A>G		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.4160+48A>G		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.4160+48A>G		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.392 AC: 57963 AN: 147794 Hom.: 12979 Cov.: 28

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.453 AC: 81083 AN: 178926 AF XY: 0.449

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.311

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.459 AC: 569495 AN: 1240214 Hom.: 144603 Cov.: 21 AF XY: 0.457 AC XY: 280967 AN XY: 614892

African (AFR) AF: 0.160 AC: 4804 AN: 30098

American (AMR) AF: 0.597 AC: 20786 AN: 34802

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 10045 AN: 21378

East Asian (EAS) AF: 0.347 AC: 12951 AN: 37354

South Asian (SAS) AF: 0.331 AC: 23659 AN: 71416

European-Finnish (FIN) AF: 0.501 AC: 22524 AN: 45000

Middle Eastern (MID) AF: 0.394 AC: 2020 AN: 5124

European-Non Finnish (NFE) AF: 0.477 AC: 449701 AN: 942190

Other (OTH) AF: 0.435 AC: 23005 AN: 52852

GnomAD4 genome AF: 0.392 AC: 57958 AN: 147898 Hom.: 12981 Cov.: 28 AF XY: 0.391 AC XY: 28081 AN XY: 71764

African (AFR) AF: 0.191 AC: 7771 AN: 40702

American (AMR) AF: 0.497 AC: 7225 AN: 14540

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1594 AN: 3402

East Asian (EAS) AF: 0.315 AC: 1552 AN: 4930

South Asian (SAS) AF: 0.326 AC: 1533 AN: 4698

European-Finnish (FIN) AF: 0.485 AC: 4707 AN: 9696

Middle Eastern (MID) AF: 0.377 AC: 107 AN: 284

European-Non Finnish (NFE) AF: 0.483 AC: 32220 AN: 66722

Other (OTH) AF: 0.414 AC: 841 AN: 2032

Alfa AF: 0.457 Hom.: 13856

Bravo AF: 0.395

Asia WGS AF: 0.286 AC: 959 AN: 3352

ClinVar

ClinVar submissions

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	-0.91
CADD	Benign	1.8
DANN	Benign	0.38
PhyloP100		-0.057
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: rs1332777; hg19: chr1-237754340; COSMIC: COSV63713040;