rs796052510

Positions:

• chr5-162149152-C-G
• chr5-162149152-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_198904.4(GABRG2):​c.967C>G​(p.Arg323Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.38

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 11 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, 8 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 chr5-162149153-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 60708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.935
• PP5: Variant 5-162149152-C-G is Pathogenic according to our data. Variant chr5-162149152-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 946639.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRG2	NM_198904.4	c.967C>G	p.Arg323Gly	missense_variant	8/10	ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2	c.967C>G	p.Arg323Gly	missense_variant	8/10	1	NM_198904.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 323 of the GABRG2 protein (p.Arg323Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABRG2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 946639). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg323 amino acid residue in GABRG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187, 27334371, 27864268, 29100083). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.5	.;.;.;.;.;.;.;.;.;.;.;D;D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	.;.;.;.;.;.;.;.;.;.;.;D;T;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0	.;.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.93
MutPred		0.79		.;.;.;.;Gain of ubiquitination at K324 (P = 0.0355);.;Gain of ubiquitination at K324 (P = 0.0355);.;Gain of ubiquitination at K324 (P = 0.0355);.;Gain of ubiquitination at K324 (P = 0.0355);.;.;Gain of ubiquitination at K324 (P = 0.0355);
MVP		0.98
MPC		2.9
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.92
gMVP		0.98

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: rs796052510; hg19: chr5-161576158;