rs41307846

Positions:

chr1-2028260-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000815.5(GABRD):c.659G>A(p.Arg220His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,611,710 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R220C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 32)

Exomes 𝑓: 0.022 ( 410 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.91

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004277706).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2540/151982) while in subpopulation NFE AF= 0.0232 (1578/67976). AF 95% confidence interval is 0.0223. There are 27 homozygotes in gnomad4. There are 1267 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5 link	c.659G>A	p.Arg220His	missense_variant	6/9	ENST00000378585.7	NP_000806.2	O14764A8K496
GABRD	XM_017000936.2 link	c.1364G>A	p.Arg455His	missense_variant	5/8		XP_016856425.1
GABRD	XM_011541194.4 link	c.698G>A	p.Arg233His	missense_variant	6/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 link	c.659G>A	p.Arg220His	missense_variant	6/9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2542

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00380

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0173

AC:

4286

AN:

248398

Hom.:

AF XY:

0.0177

AC XY:

2395

AN XY:

134944

show subpopulations

Gnomad AFR exome

AF:

0.00383

Gnomad AMR exome

AF:

0.00964

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00613

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0203

GnomAD4 exome

AF:

0.0217

AC:

31735

AN:

1459728

Hom.:

410

Cov.:

AF XY:

0.0214

AC XY:

15522

AN XY:

726134

show subpopulations

Gnomad4 AFR exome

AF:

0.00308

Gnomad4 AMR exome

AF:

0.0101

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00634

Gnomad4 FIN exome

AF:

0.0402

Gnomad4 NFE exome

AF:

0.0240

Gnomad4 OTH exome

AF:

0.0216

GnomAD4 genome

AF:

0.0167

AC:

2540

AN:

151982

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1267

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00379

Gnomad4 AMR

AF:

0.0162

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0364

Gnomad4 NFE

AF:

0.0232

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0212

Hom.:

Bravo

AF:

0.0153

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00455

AC:

ESP6500EA

AF:

0.0229

AC:

197

ExAC

AF:

0.0165

AC:

2002

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0223

EpiControl

AF:

0.0218

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 17, 2024

- -

Generalized epilepsy with febrile seizures plus type 5

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jun 01, 2005

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

GABRD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2019

This variant is classified as 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.26

T;.;.;.;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

MetaRNN

Benign

0.0043

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.56

N;.;.;.;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.42

N;.;.;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.73

T;.;.;.;.;.

Sift4G

Benign

0.65

T;.;.;.;.;.

Polyphen

0.021

B;.;.;.;.;.

Vest4

0.12

MPC

0.95

ClinPred

0.0055

GERP RS

1.5

Varity_R

0.050

gMVP

0.49

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

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