4-46332477-A-T

Position:

• chr4-46332477-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000807.4(GABRA2):​c.255+138T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 558,216 control chromosomes in the GnomAD database, including 3,700 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.088 (787 hom., cov: 32)
  • Exomes 𝑓: 0.11 (2913 hom.)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540

Genes affected

GABRA2 (HGNC:4076): (gamma-aminobutyric acid type A receptor subunit alpha2) 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4	c.255+138T>A		intron_variant		ENST00000381620.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA2	ENST00000381620.9	c.255+138T>A		intron_variant		1	NM_000807.4	P2

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13367 AN: 152060 Hom.: 789 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0434

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0958

GnomAD4 exome AF: 0.111 AC: 45256 AN: 406038 Hom.: 2913 AF XY: 0.115 AC XY: 24918 AN XY: 216040

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0391

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.0860

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0878 AC: 13354 AN: 152178 Hom.: 787 Cov.: 32 AF XY: 0.0877 AC XY: 6524 AN XY: 74392

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0435

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.0844

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.0943

Alfa AF: 0.0467 Hom.: 37

Bravo AF: 0.0849

Asia WGS AF: 0.104 AC: 362 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.39

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: rs11503016; hg19: chr4-46334494;