Genetic Variant NM_004961.4:c.1354C>G (chrX-151954868-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004961.4(GABRE):c.1354C>G(p.Arg452Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,210,144 control chromosomes in the GnomAD database, including 15 homozygotes. There are 455 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0085 ( 6 hom., 235 hem., cov: 23)

Exomes 𝑓: 0.00081 ( 9 hom. 220 hem. )

Consequence

GABRE
NM_004961.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.514

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022547245).

BP6

Variant X-151954868-G-C is Benign according to our data. Variant chrX-151954868-G-C is described in ClinVar as [Benign]. Clinvar id is 786712.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00851 (954/112128) while in subpopulation AFR AF= 0.0288 (889/30890). AF 95% confidence interval is 0.0272. There are 6 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRE	NM_004961.4 link	c.1354C>G	p.Arg452Gly	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.1354C>G	p.Arg452Gly	missense_variant	Exon 9 of 9	1	NM_004961.4	ENSP00000359353.3		P78334-1

Frequencies

GnomAD3 genomes

AF:

0.00849

AC:

951

AN:

112075

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

233

AN XY:

34265

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.0000939

Gnomad OTH

AF:

0.00742

GnomAD3 exomes

AF:

0.00208

AC:

380

AN:

182403

Hom.:

AF XY:

0.00120

AC XY:

AN XY:

66941

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000159

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.000887

GnomAD4 exome

AF:

0.000808

AC:

887

AN:

1098016

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

220

AN XY:

363378

show subpopulations

Gnomad4 AFR exome

AF:

0.0270

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000356

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00851

AC:

954

AN:

112128

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

235

AN XY:

34328

show subpopulations

Gnomad4 AFR

AF:

0.0288

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000940

Gnomad4 OTH

AF:

0.00799

Alfa

AF:

0.000793

Hom.:

Bravo

AF:

0.00939

ESP6500AA

AF:

0.0289

AC:

111

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00241

AC:

293

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.17

DANN

Benign

0.69

DEOGEN2

Benign

0.10

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.92

PrimateAI

Benign

0.21

PROVEAN

Benign

0.080

REVEL

Benign

0.15

Sift

Benign

0.42

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.031

MVP

0.76

MPC

0.074

ClinPred

0.00048

GERP RS

1.1

Varity_R

0.063

gMVP

0.25

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