Genetic Variant GABRD:p.Gly369Arg (chr1-2030028-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000815.5(GABRD):c.1105G>C(p.Gly369Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G369S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.13

Publications

1 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5 link	c.1105G>C	p.Gly369Arg	missense_variant	Exon 9 of 9	ENST00000378585.7	NP_000806.2	O14764A8K496
GABRD	XM_017000936.2 link	c.1810G>C	p.Gly604Arg	missense_variant	Exon 8 of 8		XP_016856425.1
GABRD	XM_011541194.4 link	c.1144G>C	p.Gly382Arg	missense_variant	Exon 9 of 9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 link	c.1105G>C	p.Gly369Arg	missense_variant	Exon 9 of 9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152250

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248292

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.2

L;.;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.6

N;.;.;.

REVEL

Uncertain

0.58

Sift

Benign

0.073

T;.;.;.

Sift4G

Benign

0.093

T;.;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.71

MutPred

0.54

Gain of MoRF binding (P = 0.0045);.;.;.;

MVP

0.68

MPC

2.0

ClinPred

0.91

GERP RS

3.8

Varity_R

0.14

gMVP

0.86

Mutation Taster

=49/51

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over