rs112365440

Variant names:

• chr1-237687516-C-T
• rs112365440
• NM_001035.3:c.9067+12C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001035.3(RYR2):​c.9067+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,601,008 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 1.14
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 1-237687516-C-T is Benign according to our data. Variant chr1-237687516-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43835.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (211/151940) while in subpopulation NFE AF = 0.00212 (144/67926). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 211 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.9067+12C>T		intron	N/A	NP_001026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.9067+12C>T		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.9067+12C>T		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*102+6939C>T		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 151822 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00342

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00147 AC: 352 AN: 239310 AF XY: 0.00155

Gnomad AFR exome AF: 0.000676

Gnomad AMR exome AF: 0.000505

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.00223 AC: 3234 AN: 1449068 Hom.: 5 Cov.: 29 AF XY: 0.00215 AC XY: 1551 AN XY: 720782

African (AFR) AF: 0.000811 AC: 27 AN: 33278

American (AMR) AF: 0.000567 AC: 25 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.000730 AC: 62 AN: 84910

European-Finnish (FIN) AF: 0.00279 AC: 148 AN: 53112

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5758

European-Non Finnish (NFE) AF: 0.00258 AC: 2843 AN: 1102408

Other (OTH) AF: 0.00197 AC: 118 AN: 59978

GnomAD4 genome AF: 0.00139 AC: 211 AN: 151940 Hom.: 0 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74258

African (AFR) AF: 0.000458 AC: 19 AN: 41476

American (AMR) AF: 0.000524 AC: 8 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00342 AC: 36 AN: 10530

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 67926

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	1	-	Arrhythmogenic right ventricular dysplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.74
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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: rs112365440; hg19: chr1-237850816;