1-237456575-ATTTT-ATTT

Variant names:

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

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.1477-11delT 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 0.26 (5042 hom., cov: 0)
  • Exomes 𝑓: 0.23 (3292 hom.)
• 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-AT-A is Benign according to our data. Variant chr1-237456575-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 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.1477-11delT		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.1477-24delT		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1477-24delT		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1477-24delT		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.259 AC: 38531 AN: 148980 Hom.: 5038 Cov.: 0

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.249 AC: 35330 AN: 142038 AF XY: 0.247

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.226 AC: 268933 AN: 1188048 Hom.: 3292 Cov.: 0 AF XY: 0.227 AC XY: 131607 AN XY: 580136

African (AFR) AF: 0.289 AC: 7412 AN: 25652

American (AMR) AF: 0.282 AC: 6920 AN: 24546

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 4394 AN: 19254

East Asian (EAS) AF: 0.161 AC: 5133 AN: 31822

South Asian (SAS) AF: 0.253 AC: 12696 AN: 50084

European-Finnish (FIN) AF: 0.249 AC: 9322 AN: 37392

Middle Eastern (MID) AF: 0.268 AC: 1244 AN: 4644

European-Non Finnish (NFE) AF: 0.222 AC: 210604 AN: 946570

Other (OTH) AF: 0.233 AC: 11208 AN: 48084

GnomAD4 genome AF: 0.259 AC: 38574 AN: 149064 Hom.: 5042 Cov.: 0 AF XY: 0.259 AC XY: 18809 AN XY: 72526

African (AFR) AF: 0.314 AC: 12792 AN: 40732

American (AMR) AF: 0.292 AC: 4367 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 754 AN: 3454

East Asian (EAS) AF: 0.197 AC: 990 AN: 5036

South Asian (SAS) AF: 0.255 AC: 1200 AN: 4714

European-Finnish (FIN) AF: 0.258 AC: 2474 AN: 9594

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.227 AC: 15301 AN: 67302

Other (OTH) AF: 0.250 AC: 515 AN: 2060

Alfa AF: 0.187 Hom.: 648

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (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;