rs757311213

Positions:

chr5-162153096-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_198904.4(GABRG2):c.1156C>T(p.Pro386Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GABRG2
NM_198904.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.76

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]

GABRG2 links:

GABRG2 (HGNC:):

GABRG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.28960812).

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRG2	NM_198904.4 linkuse as main transcript	c.1156C>T	p.Pro386Ser	missense_variant	10/10	ENST00000639213.2	NP_944494.1	P18507-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2 linkuse as main transcript	c.1156C>T	p.Pro386Ser	missense_variant	10/10	1	NM_198904.4	ENSP00000491909.2		P18507-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251208

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135758

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 13, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2017

A variant of uncertain significance has been identified in the GABRG2 gene. The P378S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P378S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P378S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This variant is present in population databases (rs757311213, gnomAD 0.002%). 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. 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 not expected to disrupt GABRG2 protein function. ClinVar contains an entry for this variant (Variation ID: 423505). This variant has not been reported in the literature in individuals affected with GABRG2-related conditions. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 378 of the GABRG2 protein (p.Pro378Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.28

.;.;.;.;.;T;.;.;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

T;D;T;T;T;T;D;D;D;T;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.14

.;.;.;.;.;N;.;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.60

.;.;.;.;.;.;.;.;N;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.14

.;.;.;.;.;.;.;.;T;.;.

Sift4G

Benign

0.40

.;.;.;.;.;.;.;.;T;.;.

Polyphen

0.0010, 0.0030

.;.;.;B;.;B;.;.;.;.;.

Vest4

0.46

MVP

0.93

MPC

0.63

ClinPred

0.19

GERP RS

6.0

Varity_R

0.070

gMVP

0.77

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over