NM_001035.3:c.13783-6A>G

Variant names:

• chr1-237793861-A-G
• rs790901
• NM_001035.3:c.13783-6A>G

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.13783-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,589,870 control chromosomes in the GnomAD database, including 391,473 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 0.68 (35626 hom., cov: 32)
  • Exomes 𝑓: 0.70 (355847 hom.)
• Consequence: RYR2 NM_001035.3 splice_region, intron
• Scores: Splicing: ADA: 0.000008101
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.42
• Publications: 18 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=-0.81).
• BP6: Variant 1-237793861-A-G is Benign according to our data. Variant chr1-237793861-A-G is described in ClinVar as Benign. ClinVar VariationId is 43731.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.13783-6A>G		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.13783-6A>G		splice_region intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.13801-6A>G		splice_region intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*4875-6A>G		splice_region intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103170 AN: 151848 Hom.: 35604 Cov.: 32

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.832

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.738 AC: 180422 AN: 244512 AF XY: 0.739

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.825

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.947

Gnomad FIN exome AF: 0.708

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.699 AC: 1005342 AN: 1437904 Hom.: 355847 Cov.: 28 AF XY: 0.704 AC XY: 504058 AN XY: 716162

African (AFR) AF: 0.583 AC: 19269 AN: 33038

American (AMR) AF: 0.818 AC: 36234 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 16989 AN: 25924

East Asian (EAS) AF: 0.950 AC: 37481 AN: 39464

South Asian (SAS) AF: 0.858 AC: 73301 AN: 85426

European-Finnish (FIN) AF: 0.703 AC: 37467 AN: 53278

Middle Eastern (MID) AF: 0.684 AC: 3918 AN: 5728

European-Non Finnish (NFE) AF: 0.677 AC: 739145 AN: 1091122

Other (OTH) AF: 0.697 AC: 41538 AN: 59618

GnomAD4 genome AF: 0.679 AC: 103237 AN: 151966 Hom.: 35626 Cov.: 32 AF XY: 0.686 AC XY: 50928 AN XY: 74280

African (AFR) AF: 0.590 AC: 24431 AN: 41412

American (AMR) AF: 0.750 AC: 11461 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2230 AN: 3472

East Asian (EAS) AF: 0.954 AC: 4936 AN: 5174

South Asian (SAS) AF: 0.862 AC: 4147 AN: 4810

European-Finnish (FIN) AF: 0.696 AC: 7333 AN: 10540

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46352 AN: 67966

Other (OTH) AF: 0.658 AC: 1390 AN: 2112

Alfa AF: 0.675 Hom.: 59032

Bravo AF: 0.678

Asia WGS AF: 0.877 AC: 3046 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 2 (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.58
PhyloP100		-1.4
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000081
dbscSNV1_RF	Benign	0.0
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: rs790901; hg19: chr1-237957161;