4-46259349-C-T

Variant names:

• chr4-46259349-C-T
• rs532780
• NM_000807.4:c.1059+2577G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000807.4(GABRA2):​c.1059+2577G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 151,556 control chromosomes in the GnomAD database, including 30,004 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 0.62 (30004 hom., cov: 31)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 3 publications found

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]

GABRA2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 78

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000807.4. 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
	GABRA2	NM_000807.4	MANE Select	c.1059+2577G>A		intron	N/A	NP_000798.2	P47869-1
	GABRA2	NM_001330690.2		c.1059+2577G>A		intron	N/A	NP_001317619.1	E9PBQ7
	GABRA2	NM_001377144.1		c.1059+2577G>A		intron	N/A	NP_001364073.1	E9PBQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.1059+2577G>A		intron	N/A	ENSP00000371033.4	P47869-1
	GABRA2	ENST00000507069.5	TSL:3	c.1059+2577G>A		intron	N/A	ENSP00000427603.1	E9PBQ7
	GABRA2	ENST00000863565.1		c.1137+2577G>A		intron	N/A	ENSP00000533624.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94344 AN: 151438 Hom.: 29987 Cov.: 31

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.626

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.623 AC: 94399 AN: 151556 Hom.: 30004 Cov.: 31 AF XY: 0.622 AC XY: 46104 AN XY: 74066

African (AFR) AF: 0.733 AC: 30338 AN: 41398

American (AMR) AF: 0.550 AC: 8339 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2411 AN: 3466

East Asian (EAS) AF: 0.551 AC: 2808 AN: 5094

South Asian (SAS) AF: 0.762 AC: 3665 AN: 4810

European-Finnish (FIN) AF: 0.586 AC: 6184 AN: 10556

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38585 AN: 67764

Other (OTH) AF: 0.627 AC: 1320 AN: 2106

Alfa AF: 0.466 Hom.: 1319

Bravo AF: 0.618

Asia WGS AF: 0.647 AC: 2248 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.17
PhyloP100		0.034
Mutation Taster		=100/0	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: rs532780; hg19: chr4-46261366;