5-162097663-C-T

Variant names:

• chr5-162097663-C-T
• rs772800839
• NM_198904.4:c.353C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PP3_Moderate BS2

The NM_198904.4(GABRG2):​c.353C>T​(p.Ala118Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000233 in 1,460,476 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A118A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: GABRG2 NM_198904.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.98
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 74

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 8

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• self-limited epilepsy with centrotemporal spikes

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_198904.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• BS2: High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4	c.353C>T	p.Ala118Val	missense_variant	Exon 4 of 10	ENST00000639213.2	NP_944494.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2	c.353C>T	p.Ala118Val	missense_variant	Exon 4 of 10	1	NM_198904.4	ENSP00000491909.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249424 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460476 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726608

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60328

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 Uncertain:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 118 of the GABRG2 protein (p.Ala118Val). This variant is present in population databases (rs772800839, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GABRG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 581040). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GABRG2 protein function with a positive predictive value of 95%. 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. -

Febrile seizures, familial, 8 Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

Feb 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Febrile seizures, familial, 8;C5193074:Developmental and epileptic encephalopathy, 74 Uncertain:1

Nov 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.3	.;.;.;M;.;M;.;.;.;.;M;.;.
PhyloP100		6.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	.;.;.;.;.;.;.;.;.;.;N;N;.
REVEL	Pathogenic	0.78
Sift	Benign	0.093	.;.;.;.;.;.;.;.;.;.;T;T;.
Sift4G	Benign	0.094	.;.;.;.;.;.;.;.;.;.;T;T;.
Polyphen		1.0	.;.;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.70, 0.69
MutPred		0.67		.;.;.;Loss of catalytic residue at A118 (P = 0.0887);.;Loss of catalytic residue at A118 (P = 0.0887);.;Loss of catalytic residue at A118 (P = 0.0887);.;Loss of catalytic residue at A118 (P = 0.0887);Loss of catalytic residue at A118 (P = 0.0887);Loss of catalytic residue at A118 (P = 0.0887);Loss of catalytic residue at A118 (P = 0.0887);
MVP		0.81
MPC		2.3
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.75
gMVP		0.82
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772800839; hg19: chr5-161524669; COSMIC: COSV62716849; COSMIC: COSV62716849;