Variant rs12563366 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001035.3(RYR2):c.6556-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 1,612,786 control chromosomes in the GnomAD database, including 8,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.11 ( 1251 hom., cov: 33)

Exomes 𝑓: 0.074 ( 7141 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.153

Variant links:

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 links:

RYR2 (HGNC:):

RYR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-237633550-A-G is Benign according to our data. Variant chr1-237633550-A-G is described in ClinVar as [Benign]. Clinvar id is 257213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.6556-28A>G		intron_variant		ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.6556-28A>G	intron_variant	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000609119.2 linkuse as main transcript	n.6556-28A>G	intron_variant	5		ENSP00000499659.2	A0A590UK06
RYR2	ENST00000660292.2 linkuse as main transcript	c.6556-28A>G	intron_variant			ENSP00000499787.2	A0A590UKB7
RYR2	ENST00000659194.3 linkuse as main transcript	c.6556-28A>G	intron_variant			ENSP00000499653.3	A0A590UJZ8

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16392

AN:

152106

Hom.:

1250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.155

Gnomad AMI

AF:

0.0804

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.0833

Gnomad EAS

AF:

0.342

Gnomad SAS

AF:

0.0617

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0563

Gnomad OTH

AF:

0.119

GnomAD3 exomes

AF:

0.111

AC:

27680

AN:

248400

Hom.:

2487

AF XY:

0.102

AC XY:

13761

AN XY:

134790

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.0835

Gnomad EAS exome

AF:

0.323

Gnomad SAS exome

AF:

0.0587

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.0587

Gnomad OTH exome

AF:

0.0947

GnomAD4 exome

AF:

0.0736

AC:

107520

AN:

1460562

Hom.:

7141

Cov.:

AF XY:

0.0723

AC XY:

52498

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.161

Gnomad4 AMR exome

AF:

0.206

Gnomad4 ASJ exome

AF:

0.0811

Gnomad4 EAS exome

AF:

0.395

Gnomad4 SAS exome

AF:

0.0578

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.0531

Gnomad4 OTH exome

AF:

0.0857

GnomAD4 genome

AF:

0.108

AC:

16402

AN:

152224

Hom.:

1251

Cov.:

AF XY:

0.112

AC XY:

8312

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.0833

Gnomad4 EAS

AF:

0.343

Gnomad4 SAS

AF:

0.0603

Gnomad4 FIN

AF:

0.115

Gnomad4 NFE

AF:

0.0563

Gnomad4 OTH

AF:

0.118

Alfa

AF:

0.0611

Hom.:

161

Bravo

AF:

0.118

Asia WGS

AF:

0.163

AC:

565

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

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

5.0

DANN

Benign

0.47

BranchPoint Hunter

2.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over