1-237783664-T-C

Variant names:

• chr1-237783664-T-C
• rs790889
• NM_001035.3:c.11963-11T>C

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.11963-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,562,038 control chromosomes in the GnomAD database, including 99,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9870 hom., cov: 33)
  • Exomes 𝑓: 0.35 (89859 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.001738
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.41
• Publications: 11 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: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.84).
• BP6: Variant 1-237783664-T-C is Benign according to our data. Variant chr1-237783664-T-C is described in ClinVar as Benign. ClinVar VariationId is 43716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 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.11963-11T>C		intron	N/A	NP_001026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.11963-11T>C		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.11987-11T>C		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*3055-11T>C		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53570 AN: 152004 Hom.: 9855 Cov.: 33

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.358

GnomAD2 exomes AF: 0.383 AC: 83586 AN: 218184 AF XY: 0.382

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.665

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.350 AC: 492775 AN: 1409916 Hom.: 89859 Cov.: 26 AF XY: 0.352 AC XY: 245422 AN XY: 697400

African (AFR) AF: 0.314 AC: 10141 AN: 32248

American (AMR) AF: 0.392 AC: 16048 AN: 40918

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 10943 AN: 24948

East Asian (EAS) AF: 0.693 AC: 26925 AN: 38856

South Asian (SAS) AF: 0.429 AC: 34831 AN: 81104

European-Finnish (FIN) AF: 0.345 AC: 18012 AN: 52180

Middle Eastern (MID) AF: 0.407 AC: 2280 AN: 5606

European-Non Finnish (NFE) AF: 0.327 AC: 351999 AN: 1075670

Other (OTH) AF: 0.370 AC: 21596 AN: 58386

GnomAD4 genome AF: 0.352 AC: 53622 AN: 152122 Hom.: 9870 Cov.: 33 AF XY: 0.356 AC XY: 26486 AN XY: 74342

African (AFR) AF: 0.316 AC: 13104 AN: 41520

American (AMR) AF: 0.377 AC: 5762 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1488 AN: 3468

East Asian (EAS) AF: 0.682 AC: 3523 AN: 5162

South Asian (SAS) AF: 0.434 AC: 2092 AN: 4820

European-Finnish (FIN) AF: 0.349 AC: 3690 AN: 10574

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22830 AN: 67990

Other (OTH) AF: 0.361 AC: 762 AN: 2108

Alfa AF: 0.338 Hom.: 5092

Bravo AF: 0.353

Asia WGS AF: 0.513 AC: 1784 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 2 (2)
-	-	2	not provided (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.10		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: rs790889; hg19: chr1-237946964; COSMIC: COSV63674062;