1-237730374-C-T

Variant names:

• chr1-237730374-C-T
• rs2797445
• NM_001035.3:c.10935+18C>T

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.10935+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,336,870 control chromosomes in the GnomAD database, including 664,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (73874 hom., cov: 31)
  • Exomes 𝑓: 1.0 (590400 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0490
• Publications: 9 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: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.89).
• BP6: Variant 1-237730374-C-T is Benign according to our data. Variant chr1-237730374-C-T is described in ClinVar as Benign. ClinVar VariationId is 198668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.10935+18C>T		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.10935+18C>T		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.10935+18C>T		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*1970+18C>T		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149798 AN: 152062 Hom.: 73820 Cov.: 31

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.996 AC: 244858 AN: 245794 AF XY: 0.997

Gnomad AFR exome AF: 0.946

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.998 AC: 1182701 AN: 1184690 Hom.: 590400 Cov.: 16 AF XY: 0.999 AC XY: 602164 AN XY: 603038

African (AFR) AF: 0.948 AC: 26555 AN: 28010

American (AMR) AF: 0.997 AC: 43960 AN: 44078

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 24314 AN: 24314

East Asian (EAS) AF: 1.00 AC: 38362 AN: 38362

South Asian (SAS) AF: 1.00 AC: 80365 AN: 80368

European-Finnish (FIN) AF: 1.00 AC: 52894 AN: 52894

Middle Eastern (MID) AF: 0.997 AC: 5207 AN: 5224

European-Non Finnish (NFE) AF: 1.00 AC: 859989 AN: 860172

Other (OTH) AF: 0.996 AC: 51055 AN: 51268

GnomAD4 genome AF: 0.985 AC: 149911 AN: 152180 Hom.: 73874 Cov.: 31 AF XY: 0.986 AC XY: 73383 AN XY: 74392

African (AFR) AF: 0.948 AC: 39380 AN: 41522

American (AMR) AF: 0.994 AC: 15178 AN: 15264

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 0.999 AC: 4815 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67993 AN: 68008

Other (OTH) AF: 0.990 AC: 2089 AN: 2110

Alfa AF: 0.985 Hom.: 26970

Bravo AF: 0.982

Asia WGS AF: 0.997 AC: 3467 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.23
PhyloP100		0.049
Mutation Taster		=100/0	polymorphism (auto)

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: rs2797445; hg19: chr1-237893674;