1-237566824-A-G

Variant names:

• chr1-237566824-A-G
• rs2805390
• NM_001035.3:c.3423+49A>G

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.3423+49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 1,591,350 control chromosomes in the GnomAD database, including 740,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (64074 hom., cov: 31)
  • Exomes 𝑓: 0.97 (676326 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.49
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-237566824-A-G is Benign according to our data. Variant chr1-237566824-A-G is described in ClinVar as [Benign]. Clinvar id is 257207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.3423+49A>G		intron_variant	Intron 28 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.3423+49A>G		intron_variant	Intron 28 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.3423+49A>G		intron_variant	Intron 28 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.3423+49A>G		intron_variant	Intron 28 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.912 AC: 138684 AN: 152060 Hom.: 64042 Cov.: 31

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.975

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.974

Gnomad FIN AF: 0.984

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.973

Gnomad OTH AF: 0.934

GnomAD2 exomes AF: 0.962 AC: 237833 AN: 247202 AF XY: 0.966

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.977

Gnomad ASJ exome AF: 0.977

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.981

Gnomad NFE exome AF: 0.973

Gnomad OTH exome AF: 0.965

GnomAD4 exome AF: 0.969 AC: 1394232 AN: 1439172 Hom.: 676326 Cov.: 25 AF XY: 0.970 AC XY: 695150 AN XY: 716984

African (AFR) AF: 0.738 AC: 24289 AN: 32932

American (AMR) AF: 0.975 AC: 43563 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.980 AC: 25479 AN: 26010

East Asian (EAS) AF: 1.00 AC: 39559 AN: 39566

South Asian (SAS) AF: 0.975 AC: 83359 AN: 85504

European-Finnish (FIN) AF: 0.979 AC: 52156 AN: 53272

Middle Eastern (MID) AF: 0.961 AC: 5411 AN: 5628

European-Non Finnish (NFE) AF: 0.974 AC: 1063105 AN: 1092006

Other (OTH) AF: 0.962 AC: 57311 AN: 59580

GnomAD4 genome AF: 0.912 AC: 138769 AN: 152178 Hom.: 64074 Cov.: 31 AF XY: 0.914 AC XY: 68020 AN XY: 74386

African (AFR) AF: 0.748 AC: 31014 AN: 41466

American (AMR) AF: 0.961 AC: 14689 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3409 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5158 AN: 5162

South Asian (SAS) AF: 0.975 AC: 4700 AN: 4822

European-Finnish (FIN) AF: 0.984 AC: 10437 AN: 10608

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.973 AC: 66218 AN: 68042

Other (OTH) AF: 0.934 AC: 1972 AN: 2112

Alfa AF: 0.905 Hom.: 38946

Bravo AF: 0.904

Asia WGS AF: 0.956 AC: 3323 AN: 3478

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

- -

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.095
DANN	Benign	0.44
PhyloP100		-3.5
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: rs2805390; hg19: chr1-237730124;