1-2019452-C-T

Variant names:

Variant summary

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

The NM_000815.5(GABRD):c.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 147,708 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 (★). Synonymous variant affecting the same amino acid position (i.e. P10P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 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: -0.463

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:

Genome browser will be placed here

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=0.25232822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRD	NM_000815.5 link	c.29C>T	p.Pro10Leu	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.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000206

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:

960888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

453146

African (AFR)

AF:

0.00

AC:

AN:

18766

American (AMR)

AF:

0.00

AC:

AN:

4688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9154

East Asian (EAS)

AF:

0.00

AC:

AN:

13496

South Asian (SAS)

AF:

0.00

AC:

AN:

20490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2270

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

844228

Other (OTH)

AF:

0.00

AC:

AN:

34978

GnomAD4 genome

AF:

0.0000135

AC:

AN:

147708

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

71928

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40734

American (AMR)

AF:

0.00

AC:

AN:

14916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.000206

AC:

AN:

4864

South Asian (SAS)

AF:

0.00

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66400

Other (OTH)

AF:

0.00

AC:

AN:

2026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy

Uncertain:1

Mar 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 10 of the GABRD protein (p.Pro10Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GABRD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.13

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.10

T;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.62

T;T;T;T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.20

N;.;.;.;.

PhyloP100

-0.46

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.27

N;.;.;.;.

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;.;.;.;.

Sift4G

Benign

0.22

T;.;.;.;.

Polyphen

0.0010

B;.;.;.;.

Vest4

0.19

MutPred

0.43

Loss of glycosylation at P10 (P = 0.0598);Loss of glycosylation at P10 (P = 0.0598);Loss of glycosylation at P10 (P = 0.0598);Loss of glycosylation at P10 (P = 0.0598);Loss of glycosylation at P10 (P = 0.0598);

MVP

0.44

MPC

0.77

ClinPred

0.063

GERP RS

1.9

PromoterAI

0.092

Neutral

(source)

Varity_R

0.061

gMVP

0.46

Mutation Taster

=94/6

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over