Variant 15-33613209-A-G 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_001036.6(RYR3):c.2191A>G(p.Ile731Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,612,830 control chromosomes in the GnomAD database, including 40,692 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.21 ( 3393 hom., cov: 32)

Exomes 𝑓: 0.22 ( 37299 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.446

Variant links:

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RYR3 links:

RYR3 (HGNC:):

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047627687).

BP6

Variant 15-33613209-A-G is Benign according to our data. Variant chr15-33613209-A-G is described in ClinVar as [Benign]. Clinvar id is 1166904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.2191A>G	p.Ile731Val	missense_variant	19/104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.2191A>G	p.Ile731Val	missense_variant	19/104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31366

AN:

151930

Hom.:

3386

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.218

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.278

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.230

AC:

56968

AN:

247702

Hom.:

6925

AF XY:

0.228

AC XY:

30700

AN XY:

134480

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.320

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.243

Gnomad FIN exome

AF:

0.282

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.223

AC:

325218

AN:

1460780

Hom.:

37299

Cov.:

AF XY:

0.223

AC XY:

161949

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.148

Gnomad4 AMR exome

AF:

0.316

Gnomad4 ASJ exome

AF:

0.156

Gnomad4 EAS exome

AF:

0.179

Gnomad4 SAS exome

AF:

0.245

Gnomad4 FIN exome

AF:

0.284

Gnomad4 NFE exome

AF:

0.220

Gnomad4 OTH exome

AF:

0.213

GnomAD4 genome

AF:

0.207

AC:

31408

AN:

152050

Hom.:

3393

Cov.:

AF XY:

0.211

AC XY:

15690

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.152

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.157

Gnomad4 EAS

AF:

0.159

Gnomad4 SAS

AF:

0.241

Gnomad4 FIN

AF:

0.278

Gnomad4 NFE

AF:

0.219

Gnomad4 OTH

AF:

0.193

Alfa

AF:

0.211

Hom.:

9079

Bravo

AF:

0.203

TwinsUK

AF:

0.226

AC:

837

ALSPAC

AF:

0.233

AC:

899

ESP6500AA

AF:

0.138

AC:

576

ESP6500EA

AF:

0.215

AC:

1824

ExAC

AF:

0.226

AC:

27333

Asia WGS

AF:

0.215

AC:

747

AN:

3478

EpiCase

AF:

0.208

EpiControl

AF:

0.208

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.23

T;.;.;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.76

T;T;T;T;T

MetaRNN

Benign

0.0048

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;N;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

0.25

.;N;N;.;.

REVEL

Benign

0.051

Sift

Benign

0.52

.;T;T;.;.

Polyphen

0.0

B;B;.;.;.

Vest4

0.041

MPC

0.15

ClinPred

0.0042

GERP RS

3.1

Varity_R

0.023

gMVP

0.21

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

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