rs80013027

chr1-237778645-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 257199.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-237778645-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.11776-21G>A		intron_variant		ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.11776-21G>A		intron_variant		1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.11764-21G>A		intron_variant
RYR2	ENST00000660292.2	c.11797-21G>A		intron_variant
RYR2	ENST00000609119.2	c.*2868-21G>A		intron_variant, NMD_transcript_variant		5

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

GnomAD3 exomes AF: 0.0449 AC: 10346 AN: 230516 Hom.: 297 AF XY: 0.0456 AC XY: 5715 AN XY: 125320

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 SAS exome AF: 0.0551

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

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0672

Gnomad4 SAS exome AF: 0.0512

Gnomad4 FIN exome AF: 0.0661

Gnomad4 NFE exome AF: 0.0484

Gnomad4 OTH exome AF: 0.0449

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

Gnomad4 AFR AF: 0.0317

Gnomad4 AMR AF: 0.0372

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.0608

Gnomad4 SAS AF: 0.0498

Gnomad4 FIN AF: 0.0704

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0429 Hom.: 41

Bravo AF: 0.0405

Asia WGS AF: 0.0600 AC: 208 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.12
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs80013027; hg19: chr1-237941945; COSMIC: COSV63703989;