NM_004961.4:c.1166G>C

Variant names:

• chrX-151955056-C-G
• rs745496701
• NM_004961.4:c.1166G>C

Variant summary

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

The NM_004961.4(GABRE):​c.1166G>C​(p.Arg389Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,087,787 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126
• Publications: 2 publications found

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004961.4. 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
	GABRE	NM_004961.4	MANE Select	c.1166G>C	p.Arg389Pro	missense	Exon 9 of 9	NP_004952.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRE	ENST00000370328.4	TSL:1 MANE Select	c.1166G>C	p.Arg389Pro	missense	Exon 9 of 9	ENSP00000359353.3	P78334-1
	GABRE	ENST00000486255.1	TSL:1	n.4245G>C		non_coding_transcript_exon	Exon 3 of 3
	GABRE	ENST00000483564.5	TSL:3	n.816G>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000615 AC: 1 AN: 162641 AF XY: 0.0000199

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: 0.000244

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1087787 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 1 AN XY: 354687

African (AFR) AF: 0.00 AC: 0 AN: 26280

American (AMR) AF: 0.0000291 AC: 1 AN: 34373

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18928

East Asian (EAS) AF: 0.00 AC: 0 AN: 29920

South Asian (SAS) AF: 0.00 AC: 0 AN: 52096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836542

Other (OTH) AF: 0.00 AC: 0 AN: 45656

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.0030	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.13
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.48
Sift	Benign	0.30	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.24
MutPred		0.53		Loss of helix (P = 3e-04)
MVP		0.88
MPC		0.44
ClinPred		0.36	T
GERP RS		4.6
Varity_R		0.47
gMVP		0.53
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745496701; hg19: chrX-151123528;