1-237557811-A-G

Variant names:

• chr1-237557811-A-G
• rs2805468
• NM_001035.3:c.3214+7120A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001035.3(RYR2):​c.3214+7120A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 151,818 control chromosomes in the GnomAD database, including 30,453 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (30453 hom., cov: 30)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.3214+7120A>G		intron_variant	Intron 27 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.3214+7120A>G		intron_variant	Intron 27 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.3214+7120A>G		intron_variant	Intron 27 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.3214+7120A>G		intron_variant	Intron 27 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94433 AN: 151700 Hom.: 30442 Cov.: 30

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.622 AC: 94478 AN: 151818 Hom.: 30453 Cov.: 30 AF XY: 0.623 AC XY: 46212 AN XY: 74188

African (AFR) AF: 0.442 AC: 18301 AN: 41374

American (AMR) AF: 0.612 AC: 9330 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2332 AN: 3470

East Asian (EAS) AF: 0.633 AC: 3249 AN: 5132

South Asian (SAS) AF: 0.675 AC: 3239 AN: 4796

European-Finnish (FIN) AF: 0.747 AC: 7867 AN: 10538

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.707 AC: 48070 AN: 67950

Other (OTH) AF: 0.603 AC: 1274 AN: 2112

Alfa AF: 0.673 Hom.: 111443

Bravo AF: 0.601

Asia WGS AF: 0.661 AC: 2294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.46
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: rs2805468; hg19: chr1-237721111; COSMIC: COSV63673460; COSMIC: COSV63673460;