NM_001035.3:c.849-8T>C

Variant names:

• chr1-237423084-T-C
• rs16835237
• NM_001035.3:c.849-8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.849-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,609,586 control chromosomes in the GnomAD database, including 11,647 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1118 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10529 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008724
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.429
• Publications: 14 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: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-237423084-T-C is Benign according to our data. Variant chr1-237423084-T-C is described in ClinVar as Benign. ClinVar VariationId is 43834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

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.849-8T>C		splice_region intron	N/A	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.849-8T>C		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.849-8T>C		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.849-8T>C		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15847 AN: 152082 Hom.: 1123 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0946

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.147 AC: 36047 AN: 245086 AF XY: 0.141

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.309

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.0904

Gnomad NFE exome AF: 0.0990

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.108 AC: 156751 AN: 1457386 Hom.: 10529 Cov.: 31 AF XY: 0.109 AC XY: 78877 AN XY: 724848

African (AFR) AF: 0.0626 AC: 2074 AN: 33146

American (AMR) AF: 0.299 AC: 12995 AN: 43488

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2760 AN: 25974

East Asian (EAS) AF: 0.218 AC: 8632 AN: 39658

South Asian (SAS) AF: 0.166 AC: 14147 AN: 85250

European-Finnish (FIN) AF: 0.0925 AC: 4933 AN: 53350

Middle Eastern (MID) AF: 0.150 AC: 865 AN: 5754

European-Non Finnish (NFE) AF: 0.0930 AC: 103331 AN: 1110562

Other (OTH) AF: 0.117 AC: 7014 AN: 60204

GnomAD4 genome AF: 0.104 AC: 15862 AN: 152200 Hom.: 1118 Cov.: 32 AF XY: 0.107 AC XY: 7963 AN XY: 74404

African (AFR) AF: 0.0643 AC: 2668 AN: 41516

American (AMR) AF: 0.196 AC: 3003 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3470

East Asian (EAS) AF: 0.274 AC: 1419 AN: 5180

South Asian (SAS) AF: 0.164 AC: 792 AN: 4824

European-Finnish (FIN) AF: 0.0844 AC: 895 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0946 AC: 6434 AN: 67996

Other (OTH) AF: 0.109 AC: 230 AN: 2112

Alfa AF: 0.102 Hom.: 1961

Bravo AF: 0.114

Asia WGS AF: 0.195 AC: 675 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.102

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.10		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: rs16835237; hg19: chr1-237586384; COSMIC: COSV63663128;