1-237793846-G-A

Variant names:

• chr1-237793846-G-A
• rs790902
• NM_001035.3:c.13783-21G>A

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.13783-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 1,557,336 control chromosomes in the GnomAD database, including 356,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33082 hom., cov: 32)
  • Exomes 𝑓: 0.67 (322922 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.01
• Publications: 10 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

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-237793846-G-A is Benign according to our data. Variant chr1-237793846-G-A is described in ClinVar as Benign. ClinVar VariationId is 257201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.13783-21G>A		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.13783-21G>A		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.13801-21G>A		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*4875-21G>A		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99217 AN: 151782 Hom.: 33064 Cov.: 32

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.711 AC: 164552 AN: 231294 AF XY: 0.711

Gnomad AFR exome AF: 0.542

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.680

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.673 AC: 945971 AN: 1405436 Hom.: 322922 Cov.: 23 AF XY: 0.677 AC XY: 474626 AN XY: 700558

African (AFR) AF: 0.536 AC: 17317 AN: 32278

American (AMR) AF: 0.805 AC: 34025 AN: 42286

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 15832 AN: 25570

East Asian (EAS) AF: 0.935 AC: 36532 AN: 39086

South Asian (SAS) AF: 0.821 AC: 67809 AN: 82580

European-Finnish (FIN) AF: 0.677 AC: 35862 AN: 52942

Middle Eastern (MID) AF: 0.665 AC: 3762 AN: 5656

European-Non Finnish (NFE) AF: 0.652 AC: 695679 AN: 1066650

Other (OTH) AF: 0.671 AC: 39153 AN: 58388

GnomAD4 genome AF: 0.654 AC: 99277 AN: 151900 Hom.: 33082 Cov.: 32 AF XY: 0.659 AC XY: 48914 AN XY: 74228

African (AFR) AF: 0.550 AC: 22764 AN: 41402

American (AMR) AF: 0.735 AC: 11218 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2121 AN: 3468

East Asian (EAS) AF: 0.949 AC: 4905 AN: 5168

South Asian (SAS) AF: 0.825 AC: 3978 AN: 4822

European-Finnish (FIN) AF: 0.664 AC: 6979 AN: 10512

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 45019 AN: 67956

Other (OTH) AF: 0.639 AC: 1346 AN: 2108

Alfa AF: 0.613 Hom.: 3873

Bravo AF: 0.653

Asia WGS AF: 0.856 AC: 2972 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic right ventricular dysplasia 2 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiac arrhythmia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.024
DANN	Benign	0.67
PhyloP100		-1.0
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: rs790902; hg19: chr1-237957146;