1-2030089-G-C

Position:

chr1-2030089-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000815.5(GABRD):c.1166G>C(p.Gly389Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000468 in 1,603,762 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 1 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.37

Variant links:

Genes affected

GABRD (HGNC:4084): (gamma-aminobutyric acid type A receptor subunit delta) Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

GABRD links:

GABRD (HGNC:):

GABRD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07465175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5 linkuse as main transcript	c.1166G>C	p.Gly389Ala	missense_variant	9/9	ENST00000378585.7	NP_000806.2	O14764A8K496
GABRD	XM_017000936.2 linkuse as main transcript	c.1871G>C	p.Gly624Ala	missense_variant	8/8		XP_016856425.1
GABRD	XM_011541194.4 linkuse as main transcript	c.1205G>C	p.Gly402Ala	missense_variant	9/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 linkuse as main transcript	c.1166G>C	p.Gly389Ala	missense_variant	9/9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000167

AC:

AN:

239278

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

130276

show subpopulations

Gnomad AFR exome

AF:

0.000260

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000420

AC:

AN:

1451376

Hom.:

Cov.:

AF XY:

0.0000347

AC XY:

AN XY:

721324

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.0000461

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000300

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

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

Nov 30, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

The c.1166G>C (p.G389A) alteration is located in exon 9 (coding exon 9) of the GABRD gene. This alteration results from a G to C substitution at nucleotide position 1166, causing the glycine (G) at amino acid position 389 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 389 of the GABRD protein (p.Gly389Ala). This variant is present in population databases (rs372742962, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GABRD-related conditions. ClinVar contains an entry for this variant (Variation ID: 447366). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.075

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.1

L;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.030

N;.;.;.

REVEL

Benign

0.20

Sift

Benign

0.66

T;.;.;.

Sift4G

Benign

0.78

T;.;.;.

Polyphen

0.0050

B;.;.;.

Vest4

0.30

MVP

0.63

MPC

1.1

ClinPred

0.076

GERP RS

3.8

Varity_R

0.11

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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