1-2019484-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000815.5(GABRD):c.61G>T(p.Gly21Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000679 in 147,320 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0270

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
epilepsy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
epilepsy, idiopathic generalized, susceptibility to, 10
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GABRD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5 link	c.61G>T	p.Gly21Cys	missense_variant	Exon 1 of 9	ENST00000378585.7	NP_000806.2	O14764A8K496

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 link	c.61G>T	p.Gly21Cys	missense_variant	Exon 1 of 9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.00000679

AC:

AN:

147320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

963088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

452382

African (AFR)

AF:

0.00

AC:

AN:

18920

American (AMR)

AF:

0.00

AC:

AN:

4692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9380

East Asian (EAS)

AF:

0.00

AC:

AN:

14806

South Asian (SAS)

AF:

0.00

AC:

AN:

18320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

845818

Other (OTH)

AF:

0.00

AC:

AN:

35326

GnomAD4 genome

AF:

0.00000679

AC:

AN:

147320

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

71794

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40426

American (AMR)

AF:

0.00

AC:

AN:

14902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

4762

South Asian (SAS)

AF:

0.00

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66290

Other (OTH)

AF:

0.00

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.61G>T (p.G21C) alteration is located in exon 1 (coding exon 1) of the GABRD gene. This alteration results from a G to T substitution at nucleotide position 61, causing the glycine (G) at amino acid position 21 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.31

T;T;T;T;T;D

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.30

T;T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.0

N;.;.;.;.;.

PhyloP100

0.027

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.61

N;.;.;.;.;.

REVEL

Benign

0.21

Sift

Benign

0.20

T;.;.;.;.;.

Sift4G

Benign

0.11

T;.;.;.;.;.

Polyphen

0.71

P;.;.;.;.;.

Vest4

0.14

MutPred

0.66

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;

MVP

0.67

MPC

1.5

ClinPred

0.26

GERP RS

1.9

PromoterAI

-0.036

Neutral

(source)

Varity_R

0.11

gMVP

0.54

Mutation Taster

=88/12

polymorphism

(source)

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

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1-2019484-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over