rs1060501888
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong
The NM_198904.4(GABRG2):c.1061G>T(p.Gly354Val) variant causes a missense change. 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
GABRG2
NM_198904.4 missense
NM_198904.4 missense
Scores
5
7
1
Clinical Significance
Conservation
PhyloP100: 5.66
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a helix (size 25) in uniprot entity GBRG2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_198904.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GABRG2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.816
PP5
?
Variant 5-162149246-G-T is Pathogenic according to our data. Variant chr5-162149246-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRG2 | NM_198904.4 | c.1061G>T | p.Gly354Val | missense_variant | 8/10 | ENST00000639213.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRG2 | ENST00000639213.2 | c.1061G>T | p.Gly354Val | missense_variant | 8/10 | 1 | NM_198904.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 74 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | A heterozygous missense variant, NM_000816.3(GABRG2):c.1061G>T, has been identified in exon 8 of 9 of the GABRG2 gene. The variant is predicted to result in a major amino acid change from glycine to valine at position 354 of the protein (NP_000807.2(GABRG2):p.(Gly354Val)). The glycine residue at this position has moderate conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD) and is located within a region of high missense constraint (Decipher). The variant has been previously described as likely pathogenic (ClinVar) in an individual affected with epilepsy. Analysis of parental samples indicated that this variant is de novo. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. - |
Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 12, 2018 | This sequence change replaces glycine with valine at codon 354 of the GABRG2 protein (p.Gly354Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with epilepsy (Invitae database). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
0.88, 0.95
.;.;.;.;P;.;P;.;.;.;.;.;.;.
Vest4
0.86
MutPred
0.64
.;.;.;.;Gain of catalytic residue at G354 (P = 0.0505);.;Gain of catalytic residue at G354 (P = 0.0505);.;Gain of catalytic residue at G354 (P = 0.0505);.;Gain of catalytic residue at G354 (P = 0.0505);.;.;Gain of catalytic residue at G354 (P = 0.0505);
MVP
0.92
MPC
2.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at