chr5-161689666-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000811.3(GABRA6):​c.560C>T​(p.Thr187Met) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,608,520 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T187T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (268 hom.)
• Consequence: GABRA6 NM_000811.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.82
• Publications: 12 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015738577).
• BP6: Variant 5-161689666-C-T is Benign according to our data. Variant chr5-161689666-C-T is described in ClinVar as Benign. ClinVar VariationId is 477866.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0104 (1581/152146) while in subpopulation SAS AF = 0.0472 (228/4828). AF 95% confidence interval is 0.0422. There are 10 homozygotes in GnomAd4. There are 838 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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>T	p.Thr187Met	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>T	p.Thr187Met	missense	Exon 6 of 9	ENSP00000274545.5	Q16445
	GABRA6	ENST00000523217.5	TSL:5	c.530C>T	p.Thr177Met	missense	Exon 6 of 9	ENSP00000430527.1	E7EV53
	GABRA6	ENST00000520000.5	TSL:4	c.377C>T	p.Thr126Met	missense	Exon 4 of 5	ENSP00000429943.1	H0YBP3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1582 AN: 152028 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00810

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0154 AC: 3853 AN: 250646 AF XY: 0.0175

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.00719

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00958

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.0140 AC: 20324 AN: 1456374 Hom.: 268 Cov.: 31 AF XY: 0.0150 AC XY: 10849 AN XY: 724746

African (AFR) AF: 0.00222 AC: 74 AN: 33352

American (AMR) AF: 0.00826 AC: 369 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 285 AN: 26092

East Asian (EAS) AF: 0.00651 AC: 258 AN: 39602

South Asian (SAS) AF: 0.0471 AC: 4055 AN: 86086

European-Finnish (FIN) AF: 0.0122 AC: 649 AN: 53402

Middle Eastern (MID) AF: 0.0169 AC: 97 AN: 5754

European-Non Finnish (NFE) AF: 0.0124 AC: 13681 AN: 1107180

Other (OTH) AF: 0.0142 AC: 856 AN: 60216

GnomAD4 genome AF: 0.0104 AC: 1581 AN: 152146 Hom.: 10 Cov.: 32 AF XY: 0.0113 AC XY: 838 AN XY: 74364

African (AFR) AF: 0.00291 AC: 121 AN: 41514

American (AMR) AF: 0.00772 AC: 118 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.00792 AC: 41 AN: 5176

South Asian (SAS) AF: 0.0472 AC: 228 AN: 4828

European-Finnish (FIN) AF: 0.0184 AC: 194 AN: 10562

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0120 AC: 818 AN: 68002

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0121 Hom.: 79

Bravo AF: 0.00869

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.0119 AC: 102

ExAC AF: 0.0154 AC: 1874

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Childhood absence epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.064	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.33
MPC		0.42
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.32
gMVP		0.48
Mutation Taster		=93/7	polymorphism (auto)

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: rs3811993; hg19: chr5-161116672; COSMIC: COSV99194605; COSMIC: COSV99194605;