chr1-2030125-C-T

Position:

chr1-2030125-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000815.5(GABRD):c.1202C>T(p.Thr401Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,580,476 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. T401R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0064 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 10 hom. )

Consequence

GABRD
NM_000815.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.146

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044290423).

BP6

Variant 1-2030125-C-T is Benign according to our data. Variant chr1-2030125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-2030125-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00644 (981/152280) while in subpopulation AFR AF= 0.0219 (910/41568). AF 95% confidence interval is 0.0207. There are 9 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRD	NM_000815.5 linkuse as main transcript	c.1202C>T	p.Thr401Met	missense_variant	9/9	ENST00000378585.7	NP_000806.2	O14764A8K496
GABRD	XM_017000936.2 linkuse as main transcript	c.1907C>T	p.Thr636Met	missense_variant	8/8		XP_016856425.1
GABRD	XM_011541194.4 linkuse as main transcript	c.1241C>T	p.Thr414Met	missense_variant	9/9		XP_011539496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRD	ENST00000378585.7 linkuse as main transcript	c.1202C>T	p.Thr401Met	missense_variant	9/9	1	NM_000815.5	ENSP00000367848.4		O14764

Frequencies

GnomAD3 genomes

AF:

0.00642

AC:

977

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00165

AC:

368

AN:

222654

Hom.:

AF XY:

0.00115

AC XY:

139

AN XY:

120988

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000680

Gnomad SAS exome

AF:

0.0000389

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.000720

AC:

1029

AN:

1428196

Hom.:

Cov.:

AF XY:

0.000629

AC XY:

445

AN XY:

706966

show subpopulations

Gnomad4 AFR exome

AF:

0.0198

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00239

Gnomad4 SAS exome

AF:

0.0000365

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000960

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.00644

AC:

981

AN:

152280

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

434

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0219

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00664

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00203

AC:

246

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 10

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 26, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Idiopathic generalized epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.4

DANN

Benign

0.92

DEOGEN2

Benign

0.28

T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.63

T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

L;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.53

N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.16

T;.;.;.

Sift4G

Benign

0.15

T;.;.;.

Polyphen

0.81

P;.;.;.

Vest4

0.11

MVP

0.68

MPC

0.80

ClinPred

0.0036

GERP RS

-1.9

Varity_R

0.018

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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