1-237456575-ATTTT-ATTTTT

Variant names:

• chr1-237456575-A-AT
• rs397516518
• NM_001035.3:c.1477-11dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.1477-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.53 (20698 hom., cov: 0)
  • Exomes 𝑓: 0.38 (1405 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.43
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 1-237456575-A-AT is Benign according to our data. Variant chr1-237456575-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 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.1477-11dupT		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.1477-25_1477-24insT		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1477-25_1477-24insT		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1477-25_1477-24insT		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.528 AC: 78611 AN: 148976 Hom.: 20702 Cov.: 0

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.379 AC: 53902 AN: 142038 AF XY: 0.378

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.383

Gnomad OTH exome AF: 0.365

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.384 AC: 460749 AN: 1198394 Hom.: 1405 Cov.: 0 AF XY: 0.383 AC XY: 223788 AN XY: 584872

African (AFR) AF: 0.340 AC: 8745 AN: 25734

American (AMR) AF: 0.363 AC: 8846 AN: 24344

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 7052 AN: 19366

East Asian (EAS) AF: 0.445 AC: 14188 AN: 31882

South Asian (SAS) AF: 0.337 AC: 16941 AN: 50240

European-Finnish (FIN) AF: 0.365 AC: 13668 AN: 37412

Middle Eastern (MID) AF: 0.353 AC: 1651 AN: 4678

European-Non Finnish (NFE) AF: 0.388 AC: 371284 AN: 956292

Other (OTH) AF: 0.379 AC: 18374 AN: 48446

GnomAD4 genome AF: 0.528 AC: 78635 AN: 149056 Hom.: 20698 Cov.: 0 AF XY: 0.529 AC XY: 38362 AN XY: 72500

African (AFR) AF: 0.469 AC: 19086 AN: 40732

American (AMR) AF: 0.544 AC: 8138 AN: 14962

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1885 AN: 3454

East Asian (EAS) AF: 0.682 AC: 3433 AN: 5032

South Asian (SAS) AF: 0.536 AC: 2526 AN: 4714

European-Finnish (FIN) AF: 0.542 AC: 5206 AN: 9608

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.544 AC: 36608 AN: 67296

Other (OTH) AF: 0.511 AC: 1051 AN: 2058

Alfa AF: 0.461 Hom.: 648

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
BranchPoint Hunter		3.0
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: rs397516518; hg19: chr1-237619875;