1-237259689-C-T

Variant names:

• chr1-237259689-C-T
• rs10495392
• NM_001035.3:c.49-10808C>T

Variant summary

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

The NM_001035.3(RYR2):​c.49-10808C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,200 control chromosomes in the GnomAD database, including 58,384 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 0.88 (58384 hom., cov: 31)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 5 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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.49-10808C>T		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.49-10808C>T		intron_variant	Intron 1 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.49-10808C>T		intron_variant	Intron 1 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.49-10808C>T		intron_variant	Intron 1 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133099 AN: 152080 Hom.: 58348 Cov.: 31

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.897

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.874

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.942

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.874

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

GnomAD4 genome AF: 0.875 AC: 133189 AN: 152200 Hom.: 58384 Cov.: 31 AF XY: 0.880 AC XY: 65497 AN XY: 74412

African (AFR) AF: 0.833 AC: 34616 AN: 41532

American (AMR) AF: 0.878 AC: 13419 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 3035 AN: 3472

East Asian (EAS) AF: 0.933 AC: 4803 AN: 5148

South Asian (SAS) AF: 0.942 AC: 4542 AN: 4822

European-Finnish (FIN) AF: 0.929 AC: 9850 AN: 10608

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.882 AC: 60005 AN: 68010

Other (OTH) AF: 0.875 AC: 1850 AN: 2114

Alfa AF: 0.880 Hom.: 112195

Bravo AF: 0.869

Asia WGS AF: 0.931 AC: 3240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.56
PhyloP100		-0.14
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: rs10495392; hg19: chr1-237422989;