X-151955045-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004961.4(GABRE):c.1177C>T(p.Arg393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000999 in 1,200,849 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000073 ( 0 hom. 1 hem. )

Consequence

GABRE
NM_004961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.294

Variant links:

Genes affected

GABRE (HGNC:4085): (gamma-aminobutyric acid type A receptor subunit epsilon) The product of this gene belongs to the ligand-gated ionic channel (TC 1.A.9) family. It encodes the gamma-aminobutyric acid (GABA) A receptor which is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes an epsilon subunit. It is mapped to chromosome Xq28 in a cluster comprised of genes encoding alpha 3, beta 4 and theta subunits of the same receptor. Alternatively spliced transcript variants have been identified, but only one is thought to encode a protein. [provided by RefSeq, Oct 2008]

GABRE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRE	NM_004961.4 link	c.1177C>T	p.Arg393Cys	missense_variant	Exon 9 of 9	ENST00000370328.4	NP_004952.2	P78334-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRE	ENST00000370328.4 link	c.1177C>T	p.Arg393Cys	missense_variant	Exon 9 of 9	1	NM_004961.4	ENSP00000359353.3		P78334-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111899

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000976

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000668

GnomAD2 exomes

AF:

0.00

AC:

AN:

162154

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000735

AC:

AN:

1088950

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

355490

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

AC:

AN:

26305

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

34405

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

18988

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

29957

Gnomad4 SAS exome

AF:

0.0000191

AC:

AN:

52221

Gnomad4 FIN exome

AF:

0.0000502

AC:

AN:

39859

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

837413

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

45691

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.0000357

AC:

AN:

111899

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34063

show subpopulations

Gnomad4 AFR

AF:

0.0000976

AC:

0.0000976118

AN:

0.0000976118

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000668

AC:

0.000667557

AN:

0.000667557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

GABRE-related epilepsy

Uncertain:1

Jan 07, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The maternally inherited hemizygous c.1177C>T (p.Arg393Cys) missense variant identified in the GABRE gene has not been reported in affected individuals in the literature. The variant has 0.00003575 allele frequency in the gnomAD(v3) database (4 out of 111899 heterozygous alleles, no homozygote or hemizygote) suggesting it is not a common benign variant in the populations represented in that database. The variant is located within the predicted neurotransmitter-gated ion-channel transmembrane region [2] and affects a moderately conserved residue. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 21.8, REVEL score = 0.322). Due to the lack of compelling evidence for this variant’s pathogenicity and because the disease-gene association is not yet fully established, the maternally inherited hemizygous c.1177C>T (p.Arg393Cys) missense variant identified in the GABRE gene is reported as a Variant of Uncertain Significance in a Gene of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.32

Sift

Uncertain

0.027

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.19

MutPred

0.57

Loss of methylation at R393 (P = 0.0442);

MVP

0.93

MPC

0.32

ClinPred

0.80

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.28

Mutation Taster

=89/11

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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