chr1-237064616-C-A

Variant names:

• chr1-237064616-C-A
• rs9428368
• NM_001035.3:c.48+22047C>A

Variant summary

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

The NM_001035.3(RYR2):​c.48+22047C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 151,976 control chromosomes in the GnomAD database, including 45,583 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 0.77 (45583 hom., cov: 31)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• Publications: 2 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.48+22047C>A		intron_variant	Intron 1 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.48+22047C>A		intron_variant	Intron 1 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.48+22047C>A		intron_variant	Intron 1 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.48+22047C>A		intron_variant	Intron 1 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116895 AN: 151858 Hom.: 45549 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.811

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

GnomAD4 genome AF: 0.770 AC: 116985 AN: 151976 Hom.: 45583 Cov.: 31 AF XY: 0.771 AC XY: 57247 AN XY: 74286

African (AFR) AF: 0.654 AC: 27096 AN: 41424

American (AMR) AF: 0.826 AC: 12619 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2965 AN: 3468

East Asian (EAS) AF: 0.984 AC: 5098 AN: 5180

South Asian (SAS) AF: 0.805 AC: 3881 AN: 4820

European-Finnish (FIN) AF: 0.779 AC: 8197 AN: 10522

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54375 AN: 67968

Other (OTH) AF: 0.813 AC: 1713 AN: 2108

Alfa AF: 0.796 Hom.: 206502

Bravo AF: 0.772

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.86
DANN	Benign	0.17
PhyloP100		-0.051
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: rs9428368; hg19: chr1-237227916; COSMIC: COSV63924279;