rs121909673

Positions:

• chr5-162093965-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.44

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-162093964-C-T is described in Lovd as [Likely_pathogenic].
• 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.
• 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 id is 16208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-162093965-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.245G>A	p.Arg82Gln	missense_variant	2/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.245G>A	p.Arg82Gln	missense_variant	2/10	1	NM_198904.4	ENSP00000491909	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460984 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726802

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Febrile seizures, familial, 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 27, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2023

Published functional studies demonstrate the variant disrupts GABAA receptor assembly and reduces receptor current density and current amplitude (Bianchi et al., 2002; Huang et al., 2014 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); 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, 29778030, 11326275) -

Epilepsy, childhood absence 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 27, 2013

- -

Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GABRG2 function (PMID: 11326275, 12097483, 15470132, 15866052, 16510738, 18094250, 25731747). 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 expected to disrupt GABRG2 protein function. ClinVar contains an entry for this variant (Variation ID: 16208). This variant is also known as R43Q. 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 not present in population databases (gnomAD no frequency). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.8	.;H;.;H;.;.;.;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
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	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.93

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

Other links and lift over

dbSNP: rs121909673; hg19: chr5-161520971;