NM_001035.3:c.1292+20C>T

Variant names:

• chr1-237445542-C-T
• rs182050281
• NM_001035.3:c.1292+20C>T

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.1292+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,611,854 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (96 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.376
• 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=-0.94).
• BP6: Variant 1-237445542-C-T is Benign according to our data. Variant chr1-237445542-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00565 (859/152128) while in subpopulation SAS AF = 0.0258 (124/4808). AF 95% confidence interval is 0.0221. There are 9 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 859 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.1292+20C>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.1292+20C>T		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1292+20C>T		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1292+20C>T		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 863 AN: 152010 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00768

Gnomad OTH AF: 0.00672

GnomAD2 exomes AF: 0.00810 AC: 2011 AN: 248384 AF XY: 0.00933

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00825

Gnomad OTH exome AF: 0.00947

GnomAD4 exome AF: 0.00775 AC: 11307 AN: 1459726 Hom.: 96 Cov.: 30 AF XY: 0.00850 AC XY: 6171 AN XY: 726214

African (AFR) AF: 0.00108 AC: 36 AN: 33334

American (AMR) AF: 0.00377 AC: 168 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00460 AC: 120 AN: 26068

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39634

South Asian (SAS) AF: 0.0279 AC: 2400 AN: 86106

European-Finnish (FIN) AF: 0.00184 AC: 98 AN: 53280

Middle Eastern (MID) AF: 0.0162 AC: 93 AN: 5752

European-Non Finnish (NFE) AF: 0.00711 AC: 7894 AN: 1110774

Other (OTH) AF: 0.00817 AC: 492 AN: 60242

GnomAD4 genome AF: 0.00565 AC: 859 AN: 152128 Hom.: 9 Cov.: 32 AF XY: 0.00578 AC XY: 430 AN XY: 74368

African (AFR) AF: 0.00128 AC: 53 AN: 41510

American (AMR) AF: 0.00727 AC: 111 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0258 AC: 124 AN: 4808

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10578

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00768 AC: 522 AN: 67994

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.00634 Hom.: 3

Bravo AF: 0.00517

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.17
DANN	Benign	0.55
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism

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: rs182050281; hg19: chr1-237608842;