1-2029235-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000815.5(GABRD):c.816C>T(p.Ser272Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,569,906 control chromosomes in the GnomAD database, including 20,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1800 hom., cov: 34)

Exomes 𝑓: 0.15 ( 18892 hom. )

Consequence

GABRD
NM_000815.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.476

Publications

11 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: Ambry Genetics, ClinGen
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.3176806E-5).

BP6

Variant 1-2029235-C-T is Benign according to our data. Variant chr1-2029235-C-T is described in ClinVar as Benign. ClinVar VariationId is 256825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.476 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

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.816C>T	p.Ser272Ser	synonymous	Exon 7 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.816C>T	p.Ser272Ser	synonymous	Exon 7 of 9	ENSP00000367848.4	O14764
GABRD	ENST00000638411.1	TSL:5	c.847C>T	p.Pro283Ser	missense	Exon 7 of 9	ENSP00000491632.1	A0A1W2PPP1
GABRD	ENST00000638771.1	TSL:3	c.816C>T	p.Ser272Ser	synonymous	Exon 7 of 8	ENSP00000492435.1	A0A1W2PRC4

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19216

AN:

152184

Hom.:

1790

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0316

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.147

GnomAD2 exomes

AF:

0.192

AC:

35320

AN:

184166

AF XY:

0.195

show subpopulations

Gnomad AFR exome

AF:

0.0319

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.117

Gnomad EAS exome

AF:

0.472

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.152

AC:

215491

AN:

1417604

Hom.:

18892

Cov.:

AF XY:

0.154

AC XY:

108357

AN XY:

701504

show subpopulations

African (AFR)

AF:

0.0302

AC:

975

AN:

32284

American (AMR)

AF:

0.229

AC:

8666

AN:

37870

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

2918

AN:

25470

East Asian (EAS)

AF:

0.399

AC:

14885

AN:

37260

South Asian (SAS)

AF:

0.248

AC:

20052

AN:

80986

European-Finnish (FIN)

AF:

0.174

AC:

8355

AN:

47924

Middle Eastern (MID)

AF:

0.109

AC:

625

AN:

5718

European-Non Finnish (NFE)

AF:

0.137

AC:

149751

AN:

1091132

Other (OTH)

AF:

0.157

AC:

9264

AN:

58960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

10234

20468

30701

40935

51169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5610

11220

16830

22440

28050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.126

AC:

19243

AN:

152302

Hom.:

1800

Cov.:

AF XY:

0.132

AC XY:

9853

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0315

AC:

1310

AN:

41584

American (AMR)

AF:

0.159

AC:

2433

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3472

East Asian (EAS)

AF:

0.432

AC:

2232

AN:

5164

South Asian (SAS)

AF:

0.267

AC:

1292

AN:

4832

European-Finnish (FIN)

AF:

0.176

AC:

1870

AN:

10612

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9244

AN:

68018

Other (OTH)

AF:

0.155

AC:

327

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

831

1662

2494

3325

4156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.124

Hom.:

640

Bravo

AF:

0.124

TwinsUK

AF:

0.124

AC:

461

ALSPAC

AF:

0.138

AC:

531

ESP6500AA

AF:

0.0322

AC:

141

ESP6500EA

AF:

0.131

AC:

1123

ExAC

AF:

0.157

AC:

18364

Asia WGS

AF:

0.328

AC:

1140

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Idiopathic generalized epilepsy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.2

(source)

DANN

Benign

0.72

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.24

MetaRNN

Benign

0.000043

PhyloP100

-0.48

GERP RS

-3.4

Mutation Taster

=100/0

polymorphism (auto)

(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

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over