rs121909673

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_198904.4(GABRG2):c.245G>A(p.Arg82Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GABRG2
NM_198904.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.44

Publications

42 publications found

Variant links:

Genes affected

GABRG2 (HGNC:4087): (gamma-aminobutyric acid type A receptor subunit gamma2) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRG2 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 74
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 8
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Dravet syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized epilepsy with febrile seizures plus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_198904.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-162093964-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1791457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 5-162093965-G-A is Pathogenic according to our data. Variant chr5-162093965-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4 link	c.245G>A	p.Arg82Gln	missense_variant	Exon 2 of 10	ENST00000639213.2	NP_944494.1	P18507-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2 link	c.245G>A	p.Arg82Gln	missense_variant	Exon 2 of 10	1	NM_198904.4	ENSP00000491909.2		P18507-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250890

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111428

Other (OTH)

AF:

0.00

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000841

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8

Pathogenic:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 82 of the GABRG2 protein (p.Arg82Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GABRG2-related conditions (PMID: 11326275, 31175295). It has also been observed to segregate with disease in related individuals. This variant is also known as R43Q. ClinVar contains an entry for this variant (Variation ID: 16208). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GABRG2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GABRG2 function (PMID: 11326275, 12097483, 15470132, 15866052, 16510738, 18094250, 25731747). For these reasons, this variant has been classified as Pathogenic. -

Febrile seizures, familial, 8

Pathogenic:1

Sep 27, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2

Pathogenic:1

Sep 27, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Dec 24, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate the variant disrupts GABAA receptor assembly and reduces receptor current density and current amplitude (PMID: 24798517, 12097483); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R43Q); This variant is associated with the following publications: (PMID: 28717674, 15866052, 28586508, 24630281, 17947380, 15342642, 18825662, 12097483, 15470132, 18094250, 25731747, 23408872, 25740860, 28505490, 12477709, 31440721, 31175295, 31321301, 31087664, 24798517, 11326275, 29778030) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

.;.;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.8

.;H;.;H;.;.;.;.;H;.;.

PhyloP100

9.4

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

.;.;.;.;.;.;.;.;D;D;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

.;.;.;.;.;.;.;.;D;D;.

Sift4G

Pathogenic

0.0010

.;.;.;.;.;.;.;.;D;D;.

Polyphen

1.0

.;D;.;D;.;.;.;.;.;.;.

Vest4

0.97, 0.96

MutPred

0.98

.;Loss of ubiquitination at K80 (P = 0.1191);.;Loss of ubiquitination at K80 (P = 0.1191);.;Loss of ubiquitination at K80 (P = 0.1191);.;Loss of ubiquitination at K80 (P = 0.1191);Loss of ubiquitination at K80 (P = 0.1191);Loss of ubiquitination at K80 (P = 0.1191);Loss of ubiquitination at K80 (P = 0.1191);

MVP

0.97

MPC

2.7

ClinPred

1.0

GERP RS

5.8

Varity_R

0.96

gMVP

0.93

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over