rs25409

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021912.5(GABRB3):c.31C>T(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,575,188 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 17 hom. )

Consequence

GABRB3
NM_021912.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12O:1

Conservation

PhyloP100: 1.08

Publications

30 publications found

Variant links:

Genes affected

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 43
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
epilepsy, childhood absence, susceptibility to, 5
Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006672621).

BP6

Variant 15-26773694-G-A is Benign according to our data. Variant chr15-26773694-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16191.

BS2

High AC in GnomAd4 at 532 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021912.5. 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
	GABRB3	NM_021912.5		c.31C>T	p.Pro11Ser	missense	Exon 1 of 9	NP_068712.1	X5DQY4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRB3	ENST00000299267.9	TSL:1	c.31C>T	p.Pro11Ser	missense	Exon 1 of 9	ENSP00000299267.4	P28472-2
GABRB3	ENST00000541819.6	TSL:1	c.249-922C>T		intron	N/A	ENSP00000442408.2	F5H7N0
GABRB3	ENST00000638099.1	TSL:5	c.-20+249C>T		intron	N/A	ENSP00000490678.1	A0A1B0GVW3

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

530

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00544

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00291

AC:

528

AN:

181554

AF XY:

0.00305

show subpopulations

Gnomad AFR exome

AF:

0.000854

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00332

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000726

Gnomad NFE exome

AF:

0.00472

Gnomad OTH exome

AF:

0.00350

GnomAD4 exome

AF:

0.00445

AC:

6331

AN:

1423012

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

3109

AN XY:

704018

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

32788

American (AMR)

AF:

0.00343

AC:

134

AN:

39112

Ashkenazi Jewish (ASJ)

AF:

0.00472

AC:

120

AN:

25410

East Asian (EAS)

AF:

0.00

AC:

AN:

37884

South Asian (SAS)

AF:

0.00112

AC:

AN:

80998

European-Finnish (FIN)

AF:

0.000813

AC:

AN:

49214

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00513

AC:

5607

AN:

1093188

Other (OTH)

AF:

0.00480

AC:

283

AN:

58940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

300

601

901

1202

1502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00350

AC:

532

AN:

152176

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41546

American (AMR)

AF:

0.00497

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.000196

AC:

AN:

5112

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00547

AC:

372

AN:

67988

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00417

Hom.:

Bravo

AF:

0.00376

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.00528

AC:

ExAC

AF:

0.00235

AC:

274

Asia WGS

AF:

0.000873

AC:

AN:

3452

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Epilepsy, childhood absence, susceptibility to, 1 (1)

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)

Epilepsy, childhood absence, susceptibility to, 5 (2)

Epilepsy, childhood absence, susceptibility to, 5;C4310712:Developmental and epileptic encephalopathy, 43 (1)

GABRB3-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.99

PhyloP100

1.1

PROVEAN

Benign

0.49

REVEL

Uncertain

0.44

Sift

Benign

0.70

Sift4G

Benign

0.75

Polyphen

0.14

Vest4

0.19

MVP

0.97

ClinPred

0.0029

GERP RS

2.2

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over