chr1-237832537-C-G

Variant names:

• chr1-237832537-C-G
• rs790897
• NM_001035.3:c.14809-15C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.14809-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,562,306 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (70 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.131
• Publications: 1 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=-0.78).
• BP6: Variant 1-237832537-C-G is Benign according to our data. Variant chr1-237832537-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00544 (828/152278) while in subpopulation NFE AF = 0.00967 (658/68034). AF 95% confidence interval is 0.00906. There are 1 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 828 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.14809-15C>G		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.14809-15C>G		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.14827-15C>G		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*5901-15C>G		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 830 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00967

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00547 AC: 1326 AN: 242316 AF XY: 0.00555

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00439

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00281

Gnomad NFE exome AF: 0.00877

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00831 AC: 11714 AN: 1410028 Hom.: 70 Cov.: 23 AF XY: 0.00820 AC XY: 5778 AN XY: 704670

African (AFR) AF: 0.00149 AC: 48 AN: 32268

American (AMR) AF: 0.00230 AC: 100 AN: 43422

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 109 AN: 25396

East Asian (EAS) AF: 0.000178 AC: 7 AN: 39412

South Asian (SAS) AF: 0.00466 AC: 392 AN: 84070

European-Finnish (FIN) AF: 0.00295 AC: 157 AN: 53260

Middle Eastern (MID) AF: 0.00918 AC: 52 AN: 5662

European-Non Finnish (NFE) AF: 0.00973 AC: 10391 AN: 1068148

Other (OTH) AF: 0.00784 AC: 458 AN: 58390

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74456

African (AFR) AF: 0.00178 AC: 74 AN: 41548

American (AMR) AF: 0.00190 AC: 29 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10608

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00967 AC: 658 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00848 Hom.: 0

Bravo AF: 0.00538

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	6	not specified (6)
-	-	2	Cardiomyopathy (2)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.6
DANN	Benign	0.76
PhyloP100		-0.13
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: rs790897; hg19: chr1-237995837;