5-161690237-A-C

Variant names:

• chr5-161690237-A-C
• rs76773579
• NM_000811.3:c.710A>C

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.710A>C​(p.Gln237Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. Q237R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GABRA6 NM_000811.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA6	NM_000811.3	c.710A>C	p.Gln237Pro	missense_variant	Exon 7 of 9	ENST00000274545.10	NP_000802.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA6	ENST00000274545.10	c.710A>C	p.Gln237Pro	missense_variant	Exon 7 of 9	1	NM_000811.3	ENSP00000274545.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111758

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.86
MutPred		0.78		Loss of MoRF binding (P = 0.1714);.;.;.;
MVP		0.94
MPC		0.45
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.93
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs76773579; hg19: chr5-161117243;