rs267606837

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_198904.4(GABRG2):​c.529C>G​(p.Arg177Gly) 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

GABRG2
NM_198904.4 missense

Scores

6
10
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.16
Variant links:
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 10 ACMG points.

PM1
In a topological_domain Extracellular (size 233) in uniprot entity GBRG2_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_198904.4
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, 0.947
PP5
Variant 5-162097839-C-G is Pathogenic according to our data. Variant chr5-162097839-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 16211.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-162097839-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRG2NM_198904.4 linkuse as main transcriptc.529C>G p.Arg177Gly missense_variant 4/10 ENST00000639213.2 NP_944494.1 P18507-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRG2ENST00000639213.2 linkuse as main transcriptc.529C>G p.Arg177Gly missense_variant 4/101 NM_198904.4 ENSP00000491909.2 P18507-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Febrile seizures, familial, 8 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 22, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
1.6
.;.;.;L;.;L;.;.;.;.;L;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.7
.;.;.;.;.;.;.;.;.;.;D;D;.
REVEL
Pathogenic
0.72
Sift
Benign
0.046
.;.;.;.;.;.;.;.;.;.;D;D;.
Sift4G
Uncertain
0.036
.;.;.;.;.;.;.;.;.;.;D;D;.
Polyphen
0.89, 0.91
.;.;.;P;.;P;.;.;.;.;.;.;.
Vest4
0.82, 0.77
MutPred
0.89
.;.;.;Loss of MoRF binding (P = 0.0241);.;Loss of MoRF binding (P = 0.0241);.;Loss of MoRF binding (P = 0.0241);.;Loss of MoRF binding (P = 0.0241);Loss of MoRF binding (P = 0.0241);Loss of MoRF binding (P = 0.0241);Loss of MoRF binding (P = 0.0241);
MVP
0.98
MPC
2.5
ClinPred
0.98
D
GERP RS
3.9
Varity_R
0.76
gMVP
0.90

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606837; hg19: chr5-161524845; API