rs796052505

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong

The NM_198904.4(GABRG2):c.316G>A(p.Ala106Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GABRG2
NM_198904.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 5.25

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 links:

GABRG2 (HGNC:):

GABRG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a topological_domain Extracellular (size 233) in uniprot entity GBRG2_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_198904.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRG2. . Gene score misZ 2.9939 (greater than the threshold 3.09). Trascript score misZ 3.9213 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, Dravet syndrome, undetermined early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, developmental and epileptic encephalopathy, 74, febrile seizures, familial, 8, childhood epilepsy with centrotemporal spikes.

PP5

Variant 5-162095551-G-A is Pathogenic according to our data. Variant chr5-162095551-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-162095551-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4 linkuse as main transcript	c.316G>A	p.Ala106Thr	missense_variant	3/10	ENST00000639213.2	NP_944494.1	P18507-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2 linkuse as main transcript	c.316G>A	p.Ala106Thr	missense_variant	3/10	1	NM_198904.4	ENSP00000491909.2		P18507-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721676

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	Published functional studies of A106T transfected HEK293T cells demonstrated decreased GABA-evoked whole-cell currents and altered kinetic properties of GABA-A receptor currents (Shen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29346770, 31171384, 31216405, 31087664, 30190672, 27864268, 28460589, 32901917, 32005694) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Developmental and epileptic encephalopathy, 74

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Oct 25, 2016	Rare de novo variant also identified in 4 other patients with very similar phenotype. Pathogenic given rare de novo variant also identified in four other patients with near identical phenotype, as reported in PMID 28460589. Phenotype includes early-onset seizures, global developmental delay, intellectual disability, hypotonia, movement disorder and vision issues. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000205541.11, PMID: 28460589, 27864268, 27730413, and 31216405, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 106 of the GABRG2 protein (p.Ala106Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27730413, 27864268). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205541). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GABRG2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects GABRG2 function (PMID: 27864268). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 27, 2018	GABRG2 NM_000816.3 exon 3 p.Ala106Thr (c.316G>A): This variant has been reported in the literature in 6 individuals presenting with epilepsy and other features, 5 of whom were identified as de novo (Shen 2017 PMID:27864268; Zou 2017 PMID:28460589). This variant is absent from large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 205541). Evolutionary conservation and computational predictive tools for this variant are unclear. Additionally, in vitro functional studies support that this variant will impact the protein, disrupting channel function (Shen 2017 PMID:27864268). In summary, this variant is classified as pathogenic based on the data above. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2018

The p.A106T pathogenic mutation (also known as c.316G>A), located in coding exon 3 of the GABRG2 gene, results from a G to A substitution at nucleotide position 316. The alanine at codon 106 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in multiple individuals with early-onset seizures, development delay, and hypotonia (Shen D et al. Brain, 2017 01;140:49-67; Zou F et al. J. Neurogenet. May;31:30-36). Functional studies of this mutation in HEK293T cells demonstrated a reduced surface level and altered kinetic properties (Shen D et al. Brain, 2017 01;140:49-67). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Febrile seizures, familial, 8;C5193074:Developmental and epileptic encephalopathy, 74

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 11, 2021

GABRG2 NM_000816.3 exon 3 p.Ala106Thr (c.316G>A): This variant has been reported in the literature in 6 individuals presenting with epilepsy and other features, 5 of whom were identified as de novo (Shen 2017 PMID:27864268; Zou 2017 PMID:28460589). This variant is absent from large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 205541). Evolutionary conservation and computational predictive tools for this variant are unclear. Additionally, in vitro functional studies support that this variant will impact the protein, disrupting channel function (Shen 2017 PMID:27864268). In summary, this variant is classified as pathogenic based on the data above. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

.;.;.;.;.;.;T;.;.;.;.;.;.;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.45

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

-0.20

.;.;.;.;N;.;N;.;.;.;.;N;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.010

.;.;.;.;.;.;.;.;.;.;.;N;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.85

.;.;.;.;.;.;.;.;.;.;.;T;T;.

Sift4G

Benign

0.21

.;.;.;.;.;.;.;.;.;.;.;T;T;.

Polyphen

0.092, 0.11

.;.;.;.;B;.;B;.;.;.;.;.;.;.

Vest4

0.41, 0.41

MutPred

0.47

.;.;.;.;Gain of glycosylation at A106 (P = 0.0483);.;Gain of glycosylation at A106 (P = 0.0483);.;Gain of glycosylation at A106 (P = 0.0483);.;Gain of glycosylation at A106 (P = 0.0483);Gain of glycosylation at A106 (P = 0.0483);Gain of glycosylation at A106 (P = 0.0483);Gain of glycosylation at A106 (P = 0.0483);

MVP

0.73

MPC

2.5

ClinPred

0.96

GERP RS

6.1

Varity_R

0.53

gMVP

0.63

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