1-237589774-ATT-AT

Variant names:

• chr1-237589774-AT-A
• rs11331089
• NM_001035.3:c.3599-9delT

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.3599-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11151 hom., cov: 0)
  • Exomes 𝑓: 0.44 (135317 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.467
• Publications: 2 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 1-237589774-AT-A is Benign according to our data. Variant chr1-237589774-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.463 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.3599-9delT		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.3599-18delT		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.3599-18delT		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.3599-18delT		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53178 AN: 150862 Hom.: 11148 Cov.: 0

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.324

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.456 AC: 100785 AN: 221074 AF XY: 0.453

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.309

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.479

Gnomad OTH exome AF: 0.476

GnomAD4 exome AF: 0.436 AC: 621141 AN: 1426150 Hom.: 135317 Cov.: 0 AF XY: 0.433 AC XY: 307250 AN XY: 709776

African (AFR) AF: 0.108 AC: 3484 AN: 32224

American (AMR) AF: 0.575 AC: 24991 AN: 43460

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11528 AN: 25522

East Asian (EAS) AF: 0.318 AC: 12385 AN: 38932

South Asian (SAS) AF: 0.317 AC: 26534 AN: 83604

European-Finnish (FIN) AF: 0.481 AC: 25300 AN: 52610

Middle Eastern (MID) AF: 0.352 AC: 2004 AN: 5690

European-Non Finnish (NFE) AF: 0.452 AC: 490720 AN: 1085146

Other (OTH) AF: 0.410 AC: 24195 AN: 58962

GnomAD4 genome AF: 0.352 AC: 53191 AN: 150972 Hom.: 11151 Cov.: 0 AF XY: 0.355 AC XY: 26190 AN XY: 73698

African (AFR) AF: 0.123 AC: 5031 AN: 41040

American (AMR) AF: 0.472 AC: 7153 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1543 AN: 3458

East Asian (EAS) AF: 0.287 AC: 1460 AN: 5084

South Asian (SAS) AF: 0.299 AC: 1428 AN: 4772

European-Finnish (FIN) AF: 0.481 AC: 5021 AN: 10430

Middle Eastern (MID) AF: 0.313 AC: 90 AN: 288

European-Non Finnish (NFE) AF: 0.447 AC: 30317 AN: 67756

Other (OTH) AF: 0.370 AC: 771 AN: 2084

Alfa AF: 0.330 Hom.: 1497

Bravo AF: 0.346

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
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: rs11331089; hg19: chr1-237753074; COSMIC: COSV63692546;