chr5-161689094-C-G

Variant names:

• chr5-161689094-C-G
• rs1554115593
• NM_000811.3:c.371C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000811.3(GABRA6):​c.371C>G​(p.Ser124Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRA6 NM_000811.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

Genes affected

GABRA6 (HGNC:4080): (gamma-aminobutyric acid type A receptor subunit alpha6) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. [provided by RefSeq, Jul 2008]

GABRA6-AS1 (HGNC:40248):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000811.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA6	NM_000811.3	MANE Select	c.371C>G	p.Ser124Cys	missense	Exon 4 of 9	NP_000802.2
	GABRA6-AS1	NR_189170.1		n.151+166G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA6	ENST00000274545.10	TSL:1 MANE Select	c.371C>G	p.Ser124Cys	missense	Exon 4 of 9	ENSP00000274545.5
	GABRA6	ENST00000523217.5	TSL:5	c.341C>G	p.Ser114Cys	missense	Exon 4 of 9	ENSP00000430527.1
	GABRA6	ENST00000520000.5	TSL:4	c.188C>G	p.Ser63Cys	missense	Exon 2 of 5	ENSP00000429943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood absence epilepsy Uncertain:1

Mar 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with cysteine at codon 124 of the GABRA6 protein (p.Ser124Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GABRA6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.78		Loss of disorder (P = 0.0043)
MVP		0.98
MPC		0.41
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.0056	Neutral
Varity_R		0.91
gMVP		0.68
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1554115593; hg19: chr5-161116100;