4-46337053-T-A

Variant names:

• chr4-46337053-T-A
• rs279836
• NM_000807.4:c.188-4371A>T

Variant summary

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

The ENST00000381620.9(GABRA2):​c.188-4371A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,976 control chromosomes in the GnomAD database, including 11,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.38 (11828 hom., cov: 32)
• Consequence: GABRA2 ENST00000381620.9 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -0.919
• Publications: 19 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381620.9. 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.188-4371A>T		intron	N/A	NP_000798.2
	GABRA2	NM_001330690.2		c.188-4371A>T		intron	N/A	NP_001317619.1
	GABRA2	NM_001377144.1		c.188-4371A>T		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.188-4371A>T		intron	N/A	ENSP00000371033.4
	GABRA2	ENST00000515082.5	TSL:1	c.188-4371A>T		intron	N/A	ENSP00000423840.1
	GABRA2	ENST00000507069.5	TSL:3	c.188-4371A>T		intron	N/A	ENSP00000427603.1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58197 AN: 151858 Hom.: 11814 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.316

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: 0.383 AC: 58226 AN: 151976 Hom.: 11828 Cov.: 32 AF XY: 0.385 AC XY: 28606 AN XY: 74264

African (AFR) AF: 0.258 AC: 10696 AN: 41478

American (AMR) AF: 0.457 AC: 6974 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1046 AN: 3470

East Asian (EAS) AF: 0.571 AC: 2940 AN: 5152

South Asian (SAS) AF: 0.278 AC: 1340 AN: 4826

European-Finnish (FIN) AF: 0.420 AC: 4447 AN: 10578

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29540 AN: 67906

Other (OTH) AF: 0.377 AC: 795 AN: 2110

Alfa AF: 0.412 Hom.: 1758

Bravo AF: 0.386

Asia WGS AF: 0.406 AC: 1407 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Alcoholism, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.68
PhyloP100		-0.92
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: rs279836; hg19: chr4-46339070;