4-46336282-G-C

Variant names:

• chr4-46336282-G-C
• rs279834
• NM_000807.4:c.188-3600C>G

Variant summary

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

The NM_000807.4(GABRA2):​c.188-3600C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 152,016 control chromosomes in the GnomAD database, including 11,849 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 0.38 (11849 hom., cov: 32)
• Consequence: GABRA2 NM_000807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170
• Publications: 2 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, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	NM_000807.4	MANE Select	c.188-3600C>G		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.188-3600C>G		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.188-3600C>G		intron	N/A	NP_001364073.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA2	ENST00000381620.9	TSL:1 MANE Select	c.188-3600C>G		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.188-3600C>G		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507069.5	TSL:3	c.188-3600C>G		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58350 AN: 151898 Hom.: 11835 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.384 AC: 58383 AN: 152016 Hom.: 11849 Cov.: 32 AF XY: 0.386 AC XY: 28686 AN XY: 74312

African (AFR) AF: 0.263 AC: 10915 AN: 41468

American (AMR) AF: 0.457 AC: 6974 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1045 AN: 3470

East Asian (EAS) AF: 0.558 AC: 2875 AN: 5148

South Asian (SAS) AF: 0.279 AC: 1345 AN: 4828

European-Finnish (FIN) AF: 0.420 AC: 4438 AN: 10572

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.435 AC: 29550 AN: 67952

Other (OTH) AF: 0.376 AC: 795 AN: 2114

Alfa AF: 0.412 Hom.: 1652

Bravo AF: 0.388

Asia WGS AF: 0.405 AC: 1405 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.83
DANN	Benign	0.21
PhyloP100		0.017
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: rs279834; hg19: chr4-46338299;