rs80013027

Variant names:

• chr1-237778645-G-A
• rs80013027
• NM_001035.3:c.11776-21G>A

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.11776-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,332,970 control chromosomes in the GnomAD database, including 1,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (165 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1519 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 4 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=-0.83).
• BP6: Variant 1-237778645-G-A is Benign according to our data. Variant chr1-237778645-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 257199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0552 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.11776-21G>A		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.11776-21G>A		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.11800-21G>A		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*2868-21G>A		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6731 AN: 152046 Hom.: 165 Cov.: 33

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.0512

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0449 AC: 10346 AN: 230516 AF XY: 0.0456

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0669

Gnomad FIN exome AF: 0.0701

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0477 AC: 56319 AN: 1180806 Hom.: 1519 Cov.: 15 AF XY: 0.0476 AC XY: 28249 AN XY: 592940

African (AFR) AF: 0.0286 AC: 793 AN: 27704

American (AMR) AF: 0.0192 AC: 770 AN: 40080

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 412 AN: 22982

East Asian (EAS) AF: 0.0672 AC: 2512 AN: 37364

South Asian (SAS) AF: 0.0512 AC: 3769 AN: 73602

European-Finnish (FIN) AF: 0.0661 AC: 3455 AN: 52234

Middle Eastern (MID) AF: 0.0309 AC: 157 AN: 5088

European-Non Finnish (NFE) AF: 0.0484 AC: 42197 AN: 871590

Other (OTH) AF: 0.0449 AC: 2254 AN: 50162

GnomAD4 genome AF: 0.0442 AC: 6725 AN: 152164 Hom.: 165 Cov.: 33 AF XY: 0.0457 AC XY: 3401 AN XY: 74382

African (AFR) AF: 0.0317 AC: 1318 AN: 41528

American (AMR) AF: 0.0372 AC: 568 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3468

East Asian (EAS) AF: 0.0608 AC: 314 AN: 5168

South Asian (SAS) AF: 0.0498 AC: 240 AN: 4822

European-Finnish (FIN) AF: 0.0704 AC: 745 AN: 10578

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0485 AC: 3296 AN: 68002

Other (OTH) AF: 0.0440 AC: 93 AN: 2112

Alfa AF: 0.0443 Hom.: 226

Bravo AF: 0.0405

Asia WGS AF: 0.0600 AC: 208 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.12
DANN	Benign	0.54
PhyloP100		-1.1
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: rs80013027; hg19: chr1-237941945; COSMIC: COSV63703989;