X-151969707-A-G

Variant names:

• chrX-151969707-A-G
• rs1139916
• NM_004961.4:c.304T>C

Variant summary

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

The NM_004961.4(GABRE):​c.304T>C​(p.Ser102Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S102A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GABRE NM_004961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 38 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRE	NM_004961.4	c.304T>C	p.Ser102Pro	missense_variant	Exon 3 of 9	ENST00000370328.4	NP_004952.2
GABRE	XM_024452360.2	c.-36T>C		5_prime_UTR_variant	Exon 4 of 10		XP_024308128.1
GABRE	XM_047441959.1	c.-36T>C		5_prime_UTR_variant	Exon 3 of 9		XP_047297915.1
GABRE	XM_047441960.1	c.-36T>C		5_prime_UTR_variant	Exon 2 of 9		XP_047297916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRE	ENST00000370328.4	c.304T>C	p.Ser102Pro	missense_variant	Exon 3 of 9	1	NM_004961.4	ENSP00000359353.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.066	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.57		Loss of catalytic residue at S102 (P = 0.0077);
MVP		0.87
MPC		0.28
ClinPred		0.90	D
GERP RS		2.7
Varity_R		0.90
gMVP		0.84
Mutation Taster		=296/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1139916; hg19: chrX-151138179;