GABRG2

gamma-aminobutyric acid type A receptor subunit gamma2, the group of Gamma-aminobutyric acid type A receptor subunits

Basic information

Region (hg38): 5:162000056-162162977

Links

ENSG00000113327 ∙ ∙ OMIM:137164 ∙ HGNC:4087 ∙ Uniprot:P18507 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• febrile seizures, familial, 8 (Strong), mode of inheritance: AD
• febrile seizures, familial, 8 (Strong), mode of inheritance: AD
• childhood epilepsy with centrotemporal spikes (Supportive), mode of inheritance: AD
• Dravet syndrome (Supportive), mode of inheritance: AD
• generalized epilepsy with febrile seizures plus (Supportive), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 74 (Strong), mode of inheritance: AD
• febrile seizures, familial, 8 (Strong), mode of inheritance: AD
• epilepsy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Generalized epilepsy with febrile seizures plus, type 3; Familial febrile seizures 8; Developmental and epileptic encephalopathy 74	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing; Many variants may involve a susceptibility locus and/or evidence or clinical applicability is unclear	Neurologic	11326274; 11326275; 1748509; 12117362; 17190949; 19261880; 20308251; 23069679; 27864268
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GABRG2 gene.

• Epilepsy, childhood absence 2;Febrile seizures, familial, 8 (198 variants)
• not provided (176 variants)
• Febrile seizures, familial, 8;Epilepsy, childhood absence 2 (147 variants)
• Epilepsy, childhood absence 2 (79 variants)
• Inborn genetic diseases (51 variants)
• not specified (49 variants)
• Developmental and epileptic encephalopathy, 74 (19 variants)
• Febrile seizures, familial, 8 (15 variants)
• Intellectual disability (4 variants)
• GABRG2-related condition (4 variants)
• Generalized epilepsy with febrile seizures plus (3 variants)
• Febrile seizures, familial, 8;Developmental and epileptic encephalopathy, 74 (3 variants)
• Childhood epilepsy with centrotemporal spikes (3 variants)
• Severe myoclonic epilepsy in infancy (2 variants)
• Autosomal dominant nocturnal frontal lobe epilepsy (2 variants)
• See cases (1 variants)
• Developmental and epileptic encephalopathy, 74;Febrile seizures, familial, 8 (1 variants)
• GABRG2-Related Disorder (1 variants)
• Lennox-Gastaut syndrome (1 variants)
• Generalized epilepsy with febrile seizures plus 3 (1 variants)
• Developmental and epileptic encephalopathy, 74;Epilepsy, childhood absence 2 (1 variants)
• Seizure (1 variants)
• Sudden unexplained death in childhood (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GABRG2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	78	5	89
missense	9	15	155	10	4	193
nonsense	11	10	2			23
start loss			2			2
frameshift	15	3				18
inframe indel		1	3	1		5
splice donor/acceptor (+/-2bp)	2	12	3			17
splice region		1	12	12		25
non coding			38	54	25	117
Total	37	41	209	143	34

Highest pathogenic variant AF is 0.00000657

Variants in GABRG2

This is a list of pathogenic ClinVar variants found in the GABRG2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-162067625-G-C			Likely benign (Jun 01, 2023)
5-162067645-A-C		Epilepsy, childhood absence 2	Uncertain significance (Jan 13, 2018)
5-162067666-C-T		Epilepsy, childhood absence 2	Uncertain significance (Jan 12, 2018)
5-162067718-C-T		Epilepsy, childhood absence 2	Uncertain significance (Jan 13, 2018)
5-162067732-C-A		Epilepsy, childhood absence 2	Uncertain significance (Jan 12, 2018)
5-162067750-C-T		Epilepsy, childhood absence 2	Uncertain significance (Jan 12, 2018)
5-162067759-A-C		Epilepsy, childhood absence 2	Uncertain significance (Jan 12, 2018)
5-162067783-C-G		Epilepsy, childhood absence 2	Uncertain significance (Jan 13, 2018)
5-162067804-C-T		Epilepsy, childhood absence 2	Uncertain significance (Jan 12, 2018)
5-162067821-T-A		Epilepsy, childhood absence 2	Uncertain significance (Jan 13, 2018)
5-162067846-C-T		Epilepsy, childhood absence 2	Benign (Jun 14, 2018)
5-162067886-T-C		Epilepsy, childhood absence 2	Uncertain significance (Jan 12, 2018)
5-162067896-T-G		Epilepsy, childhood absence 2	Conflicting classifications of pathogenicity (Jul 01, 2023)
5-162067984-GA-G		Severe myoclonic epilepsy in infancy • Generalized epilepsy with febrile seizures plus • Inborn genetic diseases	Conflicting classifications of pathogenicity (Feb 21, 2020)
5-162067984-G-GA		Generalized epilepsy with febrile seizures plus • Severe myoclonic epilepsy in infancy • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jul 19, 2017)
5-162068000-A-G		Epilepsy, childhood absence 2	Uncertain significance (May 28, 2019)
5-162068002-G-T		Epilepsy, childhood absence 2;Febrile seizures, familial, 8	Uncertain significance (Dec 02, 2023)
5-162068005-T-G		Epilepsy, childhood absence 2;Febrile seizures, familial, 8	Uncertain significance (Oct 26, 2022)
5-162068008-G-A		Febrile seizures, familial, 8;Epilepsy, childhood absence 2	Likely benign (Sep 21, 2022)
5-162068010-C-T		Epilepsy, childhood absence 2;Febrile seizures, familial, 8 • Inborn genetic diseases • GABRG2-related disorder	Likely benign (Oct 22, 2023)
5-162068012-A-T			Uncertain significance (Apr 10, 2020)
5-162068014-T-C		not specified	Likely benign (Jul 18, 2016)
5-162068016-T-C		Epilepsy, childhood absence 2;Febrile seizures, familial, 8	Benign (Aug 04, 2023)
5-162068020-G-C		not specified	Uncertain significance (Sep 15, 2020)
5-162068023-C-A		Epilepsy, childhood absence 2	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GABRG2	protein_coding	protein_coding	ENST00000414552	11	87997

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.739	0.261	125711	0	5	125716	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.99	137	277	0.494	0.0000152	3377
Missense in Polyphen		53	154.45	0.34316		1942
Synonymous	-0.794	108	98.0	1.10	0.00000506	970
Loss of Function	3.86	5	26.4	0.190	0.00000133	310

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000869	0.0000869
Ashkenazi Jewish	0.0000996	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000886	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand- gated chloride channel. {ECO:0000269|PubMed:2538761}.
• Disease: DISEASE: Epilepsy, childhood absence 2 (ECA2) [MIM:607681]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Some individuals manifest febrile seizures. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:11326275}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Febrile seizures, familial, 8 (FEB8) [MIM:611277]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. {ECO:0000269|PubMed:16924025}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Generalized epilepsy with febrile seizures plus 3 (GEFS+3) [MIM:611277]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:11326274, ECO:0000269|PubMed:23708187}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Benzodiazepine Pathway, Pharmacodynamics;Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Nicotine addiction - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Prader-Willi and Angelman Syndrome;Splicing factor NOVA regulated synaptic proteins;GABA receptor Signaling;GABA A receptor activation;Neuronal System;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses (Consensus)

Recessive Scores

• pRec: 0.208

Intolerance Scores

• loftool: 0.0753
• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.15

Haploinsufficiency Scores

• pHI: 0.191
• hipred: Y
• hipred_score: 0.768
• ghis: 0.650

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.780

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gabrg2
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: signal transduction;gamma-aminobutyric acid signaling pathway;chemical synaptic transmission;post-embryonic development;adult behavior;ion transmembrane transport;regulation of membrane potential;nervous system process;synaptic transmission, GABAergic;regulation of postsynaptic membrane potential;cellular response to histamine;chloride transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;cell junction;axon;cytoplasmic vesicle membrane;dendrite membrane;chloride channel complex;neuron projection;synapse;postsynaptic membrane;postsynapse;GABA-ergic synapse;GABA-A receptor complex
• Molecular function: GABA-A receptor activity;extracellular ligand-gated ion channel activity;inhibitory extracellular ligand-gated ion channel activity;chloride channel activity;protein binding;benzodiazepine receptor activity;GABA-gated chloride ion channel activity;transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential