chr1-2028259-C-T

Position:

chr1-2028259-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5BP4_StrongBP6_Very_StrongBS2

The NM_000815.5(GABRD):c.658C>T(p.Arg220Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,612,086 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. R220H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 4 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.08

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:

GABRD (HGNC:):

GABRD links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-2028260-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.044653237).

BP6

Variant 1-2028259-C-T is Benign according to our data. Variant chr1-2028259-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 529547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2028259-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5 linkuse as main transcript	c.658C>T	p.Arg220Cys	missense_variant	6/9	ENST00000378585.7	NP_000806.2	O14764A8K496
GABRD	XM_017000936.2 linkuse as main transcript	c.1363C>T	p.Arg455Cys	missense_variant	5/8		XP_016856425.1
GABRD	XM_011541194.4 linkuse as main transcript	c.697C>T	p.Arg233Cys	missense_variant	6/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 linkuse as main transcript	c.658C>T	p.Arg220Cys	missense_variant	6/9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000934

AC:

232

AN:

248518

Hom.:

AF XY:

0.000926

AC XY:

125

AN XY:

135012

show subpopulations

Gnomad AFR exome

AF:

0.000314

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00141

AC:

2057

AN:

1459850

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

1035

AN XY:

726200

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.000365

Gnomad4 NFE exome

AF:

0.00164

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152236

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000916

AC:

111

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2023	- -

GABRD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.29

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.045

ClinPred

0.048

GERP RS

3.5

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