5-162151741-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_198904.4(GABRG2):​c.1140G>T​(p.Met380Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GABRG2
NM_198904.4 missense

Scores

1
4
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.52
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the GABRG2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.9939 (below the threshold of 3.09). Trascript score misZ: 3.9213 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.41887903).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GABRG2NM_198904.4 linkc.1140G>T p.Met380Ile missense_variant Exon 9 of 10 ENST00000639213.2 NP_944494.1 P18507-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GABRG2ENST00000639213.2 linkc.1140G>T p.Met380Ile missense_variant Exon 9 of 10 1 NM_198904.4 ENSP00000491909.2 P18507-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458296
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
725424
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000254
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Benign
0.96
Eigen
Benign
-0.013
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
T;T;T;T;T;T
M_CAP
Benign
0.046
D
MetaRNN
Benign
0.42
T;T;T;T;T;T
MetaSVM
Benign
-0.99
T
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.48
.;.;.;.;.;N
REVEL
Uncertain
0.33
Sift
Benign
0.21
.;.;.;.;.;T
Sift4G
Benign
0.28
.;.;.;.;.;T
Polyphen
0.0
.;B;.;.;.;.
Vest4
0.63
MutPred
0.52
.;Loss of disorder (P = 0.065);.;Loss of disorder (P = 0.065);.;.;
MVP
0.86
MPC
0.56
ClinPred
0.99
D
GERP RS
5.8
gMVP
0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-161578747; API