rs1057520498

Positions:

• chr5-162095504-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001375349.1(GABRG2):​c.-17C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,292 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GABRG2 NM_001375349.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 7.48

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 5-162095504-C-T is Pathogenic according to our data. Variant chr5-162095504-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 379114.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.269C>T	p.Thr90Met	missense_variant	3/10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.269C>T	p.Thr90Met	missense_variant	3/10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249666 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134976

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452292 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 3 AN XY: 723148

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Febrile seizures, familial, 8 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.721>=0.6, 3CNET: 0.803>=0.75). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GABRG2 related disorder (PMID:33391346). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Autosomal dominant nocturnal frontal lobe epilepsy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing;in vitro

Wen Jiang Lab, Comprehensive Epilepsy Center, Xijing Hospital

Feb 09, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2024

Published functional studies demonstrate that this variant significantly impairs cell trafficking and causes GABRG2 subunits to be retained in the endoplasmic reticulum, resulting in decreased surface expression and reduced peak currents (PMID: 35486215); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33726816, 34095830, 35605087, 31440721, 35359574, 35486215, 33391346) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 90 of the GABRG2 protein (p.Thr90Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of GABRG2-related conditions (PMID: 33391346; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 379114). 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.2	.;M;.;M;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.9	.;.;.;.;.;.;.;.;D;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;D;D;.
Sift4G	Pathogenic	0.0010	.;.;.;.;.;.;.;.;D;D;.
Polyphen		1.0	.;D;.;D;.;.;.;.;.;.;.
Vest4		0.86, 0.87
MutPred		0.56		.;Gain of ubiquitination at K88 (P = 0.1797);.;Gain of ubiquitination at K88 (P = 0.1797);.;Gain of ubiquitination at K88 (P = 0.1797);.;Gain of ubiquitination at K88 (P = 0.1797);Gain of ubiquitination at K88 (P = 0.1797);Gain of ubiquitination at K88 (P = 0.1797);Gain of ubiquitination at K88 (P = 0.1797);
MVP		0.89
MPC		2.6
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.85
gMVP		0.85

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: rs1057520498; hg19: chr5-161522510; COSMIC: COSV62719464; COSMIC: COSV62719464;