rs1881548

Variant names:

• chr1-237043889-A-G
• rs1881548
• NM_001035.3:c.48+1320A>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.48+1320A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 152,252 control chromosomes in the GnomAD database, including 2,898 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 0.17 (2898 hom., cov: 33)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• 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=-0.77).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.48+1320A>G		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+1320A>G		intron_variant	Intron 1 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.48+1320A>G		intron_variant	Intron 1 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.48+1320A>G		intron_variant	Intron 1 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25637 AN: 152134 Hom.: 2895 Cov.: 33

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.168 AC: 25643 AN: 152252 Hom.: 2898 Cov.: 33 AF XY: 0.170 AC XY: 12653 AN XY: 74456

African (AFR) AF: 0.0483 AC: 2007 AN: 41548

American (AMR) AF: 0.297 AC: 4538 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 765 AN: 3472

East Asian (EAS) AF: 0.185 AC: 959 AN: 5184

South Asian (SAS) AF: 0.377 AC: 1819 AN: 4824

European-Finnish (FIN) AF: 0.0993 AC: 1054 AN: 10614

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13795 AN: 68002

Other (OTH) AF: 0.189 AC: 399 AN: 2116

Alfa AF: 0.207 Hom.: 6132

Bravo AF: 0.176

Asia WGS AF: 0.276 AC: 960 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.2
DANN	Benign	0.71
PhyloP100		0.055
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: rs1881548; hg19: chr1-237207189;