Variant X-151955051-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004961.4(GABRE):c.1171C>T(p.Arg391Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,088,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000028 ( 0 hom. 2 hem. )

Consequence

GABRE
NM_004961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.256

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3077577).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRE	NM_004961.4 linkuse as main transcript	c.1171C>T	p.Arg391Cys	missense_variant	9/9	ENST00000370328.4	NP_004952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRE	ENST00000370328.4 linkuse as main transcript	c.1171C>T	p.Arg391Cys	missense_variant	9/9	1	NM_004961.4	ENSP00000359353	P1	P78334-1
GABRE	ENST00000486255.1 linkuse as main transcript	n.4250C>T		non_coding_transcript_exon_variant	3/3	1
GABRE	ENST00000483564.5 linkuse as main transcript	n.821C>T		non_coding_transcript_exon_variant	4/4	3
GABRE	ENST00000495862.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

163320

Hom.:

AF XY:

0.0000197

AC XY:

AN XY:

50794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000154

Gnomad SAS 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:

0.00000276

AC:

AN:

1088772

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

355402

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000668

Gnomad4 SAS exome

AF:

0.0000191

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.1171C>T (p.R391C) alteration is located in exon 9 (coding exon 9) of the GABRE gene. This alteration results from a C to T substitution at nucleotide position 1171, causing the arginine (R) at amino acid position 391 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

REVEL

Benign

0.26

Sift

Benign

0.048

Sift4G

Uncertain

0.042

Polyphen

1.0

Vest4

0.11

MutPred

0.54

Loss of methylation at R391 (P = 0.0384);

MVP

0.88

MPC

0.079

ClinPred

0.29

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.096

gMVP

0.27

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