NM_000815.5:c.54G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000815.5(GABRD):c.54G>T(p.Gln18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,113,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.626

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: Labcorp Genetics (formerly Invitae), Ambry Genetics

GABRD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14740586).

BS2

High AC in GnomAdExome4 at 34 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000815.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRD	NM_000815.5	MANE Select	c.54G>T	p.Gln18His	missense	Exon 1 of 9	NP_000806.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRD	ENST00000378585.7	TSL:1 MANE Select	c.54G>T	p.Gln18His	missense	Exon 1 of 9	ENSP00000367848.4	O14764
GABRD	ENST00000638771.1	TSL:3	c.54G>T	p.Gln18His	missense	Exon 1 of 8	ENSP00000492435.1	A0A1W2PRC4
GABRD	ENST00000640067.1	TSL:5	c.54G>T	p.Gln18His	missense	Exon 1 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000490

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000352

AC:

AN:

965270

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

453744

show subpopulations

African (AFR)

AF:

0.0000527

AC:

AN:

18992

American (AMR)

AF:

0.00

AC:

AN:

4774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9422

East Asian (EAS)

AF:

0.00

AC:

AN:

14888

South Asian (SAS)

AF:

0.00

AC:

AN:

18550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2306

European-Non Finnish (NFE)

AF:

0.0000390

AC:

AN:

847106

Other (OTH)

AF:

0.00

AC:

AN:

35534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000202

AC:

AN:

148412

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72372

show subpopulations

African (AFR)

AF:

0.0000490

AC:

AN:

40832

American (AMR)

AF:

0.00

AC:

AN:

14992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

4892

South Asian (SAS)

AF:

0.00

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66580

Other (OTH)

AF:

0.00

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Idiopathic generalized epilepsy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.6

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.11

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PhyloP100

0.63

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.17

REVEL

Benign

0.11

Sift

Benign

0.21

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.14

MutPred

0.46

Loss of helix (P = 0.028)

MVP

0.22

MPC

0.71

ClinPred

0.033

GERP RS

-0.32

PromoterAI

-0.071

Neutral

(source)

Varity_R

0.044

gMVP

0.47

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over