Genetic Variant GABRD:p.Ala5Val (chr1-2019437-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000815.5(GABRD):c.14C>T(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. A5G) has been classified as Uncertain significance.

Frequency

Genomes: not found (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: -0.260

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: ClinGen, Ambry Genetics
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:

ENSG00000233542 (HGNC:):

ENSG00000233542 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18545806).

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.14C>T	p.Ala5Val	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.14C>T	p.Ala5Val	missense	Exon 1 of 9	ENSP00000367848.4	O14764
GABRD	ENST00000638771.1	TSL:3	c.14C>T	p.Ala5Val	missense	Exon 1 of 8	ENSP00000492435.1	A0A1W2PRC4
GABRD	ENST00000640067.1	TSL:5	c.14C>T	p.Ala5Val	missense	Exon 1 of 9	ENSP00000491844.1	A0A1W2PQR3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

954514

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

451372

African (AFR)

AF:

0.00

AC:

AN:

18428

American (AMR)

AF:

0.00

AC:

AN:

4714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8832

East Asian (EAS)

AF:

0.00

AC:

AN:

12102

South Asian (SAS)

AF:

0.00

AC:

AN:

21534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840446

Other (OTH)

AF:

0.00

AC:

AN:

34488

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Idiopathic generalized epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.55

PhyloP100

-0.26

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.31

REVEL

Benign

0.14

Sift

Benign

0.13

Sift4G

Benign

0.27

Polyphen

0.0060

Vest4

0.15

MutPred

0.31

Loss of disorder (P = 0.0682)

MVP

0.76

MPC

0.75

ClinPred

0.092

GERP RS

0.54

PromoterAI

0.0036

Neutral

(source)

Varity_R

0.042

gMVP

0.52

Mutation Taster

=91/9

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over