chr1-237794009-A-C

Variant names:

• chr1-237794009-A-C
• rs790900
• NM_001035.3:c.13913+12A>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.13913+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,601,696 control chromosomes in the GnomAD database, including 384,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35105 hom., cov: 32)
  • Exomes 𝑓: 0.69 (349144 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.00600
• Publications: 13 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

ENSG00000296715 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-237794009-A-C is Benign according to our data. Variant chr1-237794009-A-C is described in ClinVar as Benign. ClinVar VariationId is 43732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 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.13913+12A>C		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.13913+12A>C		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.13931+12A>C		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*5005+12A>C		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102503 AN: 151808 Hom.: 35082 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.651

GnomAD2 exomes AF: 0.732 AC: 179175 AN: 244682 AF XY: 0.732

Gnomad AFR exome AF: 0.598

Gnomad AMR exome AF: 0.823

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.947

Gnomad FIN exome AF: 0.707

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.697

GnomAD4 exome AF: 0.690 AC: 1000578 AN: 1449770 Hom.: 349144 Cov.: 28 AF XY: 0.694 AC XY: 501080 AN XY: 721584

African (AFR) AF: 0.595 AC: 19718 AN: 33122

American (AMR) AF: 0.815 AC: 36007 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 16948 AN: 25990

East Asian (EAS) AF: 0.950 AC: 37597 AN: 39582

South Asian (SAS) AF: 0.840 AC: 71592 AN: 85196

European-Finnish (FIN) AF: 0.702 AC: 37328 AN: 53170

Middle Eastern (MID) AF: 0.670 AC: 3848 AN: 5746

European-Non Finnish (NFE) AF: 0.668 AC: 736225 AN: 1102830

Other (OTH) AF: 0.689 AC: 41315 AN: 59954

GnomAD4 genome AF: 0.675 AC: 102572 AN: 151926 Hom.: 35105 Cov.: 32 AF XY: 0.682 AC XY: 50605 AN XY: 74224

African (AFR) AF: 0.599 AC: 24792 AN: 41422

American (AMR) AF: 0.742 AC: 11309 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2213 AN: 3462

East Asian (EAS) AF: 0.954 AC: 4929 AN: 5166

South Asian (SAS) AF: 0.844 AC: 4064 AN: 4814

European-Finnish (FIN) AF: 0.694 AC: 7321 AN: 10544

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45676 AN: 67966

Other (OTH) AF: 0.655 AC: 1380 AN: 2108

Alfa AF: 0.679 Hom.: 30271

Bravo AF: 0.675

Asia WGS AF: 0.872 AC: 3028 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 2 (2)
-	-	2	not provided (2)
-	-	1	Cardiac arrhythmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.4
DANN	Benign	0.72
PhyloP100		0.0060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs790900; hg19: chr1-237957309;