rs79386457

Positions:

chr1-2030073-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_000815.5(GABRD):c.1150C>T(p.Pro384Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,608,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P384L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.91

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015913546).

BP6

Variant 1-2030073-C-T is Benign according to our data. Variant chr1-2030073-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GABRD	NM_000815.5 linkuse as main transcript	c.1150C>T	p.Pro384Ser	missense_variant	9/9	ENST00000378585.7
GABRD	XM_017000936.2 linkuse as main transcript	c.1855C>T	p.Pro619Ser	missense_variant	8/8
GABRD	XM_011541194.4 linkuse as main transcript	c.1189C>T	p.Pro397Ser	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRD	ENST00000378585.7 linkuse as main transcript	c.1150C>T	p.Pro384Ser	missense_variant	9/9	1	NM_000815.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000657

AC:

160

AN:

243610

Hom.:

AF XY:

0.000700

AC XY:

AN XY:

132788

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000921

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.000635

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000450

AC:

655

AN:

1456618

Hom.:

Cov.:

AF XY:

0.000491

AC XY:

356

AN XY:

724476

show subpopulations

Gnomad4 AFR exome

AF:

0.000480

Gnomad4 AMR exome

AF:

0.000773

Gnomad4 ASJ exome

AF:

0.00197

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000607

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000349

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000506

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000487

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000620

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

GABRD-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic generalized epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.4

DANN

Benign

0.92

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.016

T;T

MutationTaster

Benign

0.97

ClinPred

0.010

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over