X-151954868-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.514

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

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 GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRE	NM_004961.4	c.1354C>G	p.Arg452Gly	missense_variant	9/9	ENST00000370328.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRE	ENST00000370328.4	c.1354C>G	p.Arg452Gly	missense_variant	9/9	1	NM_004961.4	P1
GABRE	ENST00000486255.1	n.4433C>G		non_coding_transcript_exon_variant	3/3	1
GABRE	ENST00000483564.5	n.1004C>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 951 AN: 112075 Hom.: 6 Cov.: 23 AF XY: 0.00680 AC XY: 233 AN XY: 34265

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.: 5 AF XY: 0.00120 AC XY: 80 AN XY: 66941

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.: 9 Cov.: 32 AF XY: 0.000605 AC XY: 220 AN XY: 363378

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.: 6 Cov.: 23 AF XY: 0.00685 AC XY: 235 AN XY: 34328

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.: 21

Bravo AF: 0.00939

ESP6500AA AF: 0.0289 AC: 111

ESP6500EA AF: 0.000149 AC: 1

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 03, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.17
Dann	Benign	0.69
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.92	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.15
Sift	Benign	0.42	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.031
MVP		0.76
MPC		0.074
ClinPred		0.00048	T
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

Other links and lift over

dbSNP: rs61730044; hg19: chrX-151123340;