rs1554100910

Positions:

• chr5-162149112-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The ENST00000639213.2(GABRG2):​c.927C>G​(p.Ile309Met) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I309T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRG2 ENST00000639213.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.493

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 Likely_pathogenic. Variant got 7 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, 10 uncertain in ENST00000639213.2
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.927C>G	p.Ile309Met	missense_variant	8/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.927C>G	p.Ile309Met	missense_variant	8/10	1	NM_198904.4	ENSP00000491909	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 536743). This variant has not been reported in the literature in individuals affected with GABRG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 309 of the GABRG2 protein (p.Ile309Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T;D;D;T;T;T;D;D;D;D;T;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	.;.;.;.;.;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0010	.;.;.;.;.;.;.;.;.;.;.;D;.;.
Polyphen		1.0	.;.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.83		.;.;.;.;Loss of stability (P = 0.0451);.;Loss of stability (P = 0.0451);.;Loss of stability (P = 0.0451);.;Loss of stability (P = 0.0451);.;.;Loss of stability (P = 0.0451);
MVP		0.92
MPC		2.6
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.90
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: rs1554100910; hg19: chr5-161576118;