rs25409

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_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. 10/13 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in the GABRB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.3856 (above the threshold of 3.09). Trascript score misZ: 4.3655 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, developmental and epileptic encephalopathy, 43, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, epilepsy, childhood absence, susceptibility to, 5.

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 id is 16191.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=7, Uncertain_significance=1}. Variant chr15-26773694-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 532 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_021912.5 link	c.31C>T	p.Pro11Ser	missense_variant	Exon 1 of 9		NP_068712.1	P28472-2B2RCW8X5DQY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
GABRB3	ENST00000299267.9 link	c.31C>T	p.Pro11Ser	missense_variant	Exon 1 of 9	1	ENSP00000299267.4	P28472-2
GABRB3	ENST00000541819.6 link	c.249-922C>T		intron_variant	Intron 2 of 9	1	ENSP00000442408.2	F5H7N0
GABRB3	ENST00000638099.1 link	c.-20+249C>T		intron_variant	Intron 1 of 8	5	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

GnomAD3 exomes

AF:

0.00291

AC:

528

AN:

181554

Hom.:

AF XY:

0.00305

AC XY:

299

AN XY:

98054

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 SAS exome

AF:

0.000892

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

Gnomad4 AFR exome

AF:

0.00113

Gnomad4 AMR exome

AF:

0.00343

Gnomad4 ASJ exome

AF:

0.00472

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.000813

Gnomad4 NFE exome

AF:

0.00513

Gnomad4 OTH exome

AF:

0.00480

GnomAD4 genome

AF:

0.00350

AC:

532

AN:

152176

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00497

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00547

Gnomad4 OTH

AF:

0.00474

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABRB3: PP2, BP4, BS1, BS2 -

Apr 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26645412, 22206818, 20550555, 19935738, 18514161, 20308251, 27884173, 31435640) -

Oct 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 5

Uncertain:1Other:1

Jun 01, 2008

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 02, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Dec 02, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

GABRB3-related disorder

Benign:1

Jun 05, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Oct 24, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABRB3 NM_021912.5 exon 1 p.Pro11Ser (c.31C>T): This variant has been reported in the literature in at least 2 individuals with absence epilepsy and numerous individuals with autism (Tanaka 2008 PMID:185141461, Delahanty 2011 PMID:19935738). However, this variant is present in 0.5% (370/67998) of European alleles including 2 homozygotes, as well as 1 homozygote in the South Asian population in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-26773694-G-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:16191). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies suggests that this variant may impact the protein, however, this data may not represent in vivo biological function (Tanaka 2008 PMID:185141461, Shi 2019 PMID:31435640). In summary, data on this variant, particularly the minor allele frequency and presence of homozygotes in ostensibly unaffected individuals suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as Likely Benign. -

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

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 1

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

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

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

Splicing

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