5-161689666-C-G

Variant names:

• chr5-161689666-C-G
• rs3811993
• NM_000811.3:c.560C>G

Variant summary

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

The NM_000811.3(GABRA6):​c.560C>G​(p.Thr187Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T187M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GABRA6 NM_000811.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.82
• 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]

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_000811.3. 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
	GABRA6	NM_000811.3	MANE Select	c.560C>G	p.Thr187Arg	missense	Exon 6 of 9	NP_000802.2	Q16445

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA6	ENST00000274545.10	TSL:1 MANE Select	c.560C>G	p.Thr187Arg	missense	Exon 6 of 9	ENSP00000274545.5	Q16445
	GABRA6	ENST00000523217.5	TSL:5	c.530C>G	p.Thr177Arg	missense	Exon 6 of 9	ENSP00000430527.1	E7EV53
	GABRA6	ENST00000520000.5	TSL:4	c.377C>G	p.Thr126Arg	missense	Exon 4 of 5	ENSP00000429943.1	H0YBP3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724910

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107486

Other (OTH) AF: 0.00 AC: 0 AN: 60224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.42
Sift	Benign	0.60	T
Sift4G	Benign	0.55	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.36		Gain of MoRF binding (P = 0.0436)
MVP		0.86
MPC		0.44
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.68
gMVP		0.67
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs3811993; hg19: chr5-161116672;