chr1-237602011-TA-T

Variant names:

• chr1-237602011-TA-T
• rs3841805
• NM_001035.3:c.4597-11delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.4597-11delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,605,380 control chromosomes in the GnomAD database, including 90 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (61 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.487
• 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: 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 -16 ACMG points.

• BP6: Variant 1-237602011-TA-T is Benign according to our data. Variant chr1-237602011-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.011 (1670/152308) while in subpopulation EAS AF = 0.0357 (185/5184). AF 95% confidence interval is 0.0315. There are 29 homozygotes in GnomAd4. There are 775 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1670 AD gene.

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.4597-11delA		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.4597-13delA		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.4597-13delA		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.4597-13delA		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1674 AN: 152190 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0360

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.00532 AC: 1304 AN: 244908 AF XY: 0.00432

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.0331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00210 AC: 3054 AN: 1453072 Hom.: 61 Cov.: 29 AF XY: 0.00199 AC XY: 1435 AN XY: 722876

African (AFR) AF: 0.0301 AC: 1002 AN: 33276

American (AMR) AF: 0.00274 AC: 121 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.000270 AC: 7 AN: 25926

East Asian (EAS) AF: 0.0372 AC: 1470 AN: 39472

South Asian (SAS) AF: 0.00115 AC: 98 AN: 84944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5736

European-Non Finnish (NFE) AF: 0.0000642 AC: 71 AN: 1106290

Other (OTH) AF: 0.00456 AC: 274 AN: 60022

GnomAD4 genome AF: 0.0110 AC: 1670 AN: 152308 Hom.: 29 Cov.: 33 AF XY: 0.0104 AC XY: 775 AN XY: 74480

African (AFR) AF: 0.0330 AC: 1371 AN: 41578

American (AMR) AF: 0.00451 AC: 69 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0357 AC: 185 AN: 5184

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68014

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00547 Hom.: 2

Bravo AF: 0.0131

Asia WGS AF: 0.0200 AC: 68 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.49
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: rs3841805; hg19: chr1-237765311;