Genetic Variant GABRA2:c.188-3T>C (chr4-46332685-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000807.4(GABRA2):c.188-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,516,768 control chromosomes in the GnomAD database, including 148,881 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13516 hom., cov: 32)

Exomes 𝑓: 0.44 ( 135365 hom. )

Consequence

GABRA2
NM_000807.4 splice_region, intron

Scores

Splicing: ADA: 0.0001221

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.75

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 4-46332685-A-G is Benign according to our data. Variant chr4-46332685-A-G is described in ClinVar as [Benign]. Clinvar id is 1168078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4 link	c.188-3T>C		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000381620.9	NP_000798.2	P47869-1A0A024R9X6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9 link	c.188-3T>C		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_000807.4	ENSP00000371033.4		P47869-1

Frequencies

GnomAD3 genomes

AF:

0.415

AC:

62955

AN:

151810

Hom.:

13497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.470

Gnomad ASJ

AF:

0.322

Gnomad EAS

AF:

0.561

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.471

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.457

Gnomad OTH

AF:

0.398

GnomAD3 exomes

AF:

0.437

AC:

108330

AN:

247996

Hom.:

24545

AF XY:

0.429

AC XY:

57493

AN XY:

134130

show subpopulations

Gnomad AFR exome

AF:

0.316

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.326

Gnomad EAS exome

AF:

0.565

Gnomad SAS exome

AF:

0.303

Gnomad FIN exome

AF:

0.478

Gnomad NFE exome

AF:

0.447

Gnomad OTH exome

AF:

0.430

GnomAD4 exome

AF:

0.440

AC:

600608

AN:

1364842

Hom.:

135365

Cov.:

AF XY:

0.436

AC XY:

298136

AN XY:

684556

show subpopulations

Gnomad4 AFR exome

AF:

0.296

Gnomad4 AMR exome

AF:

0.510

Gnomad4 ASJ exome

AF:

0.330

Gnomad4 EAS exome

AF:

0.520

Gnomad4 SAS exome

AF:

0.306

Gnomad4 FIN exome

AF:

0.475

Gnomad4 NFE exome

AF:

0.451

Gnomad4 OTH exome

AF:

0.435

GnomAD4 genome

AF:

0.415

AC:

63010

AN:

151926

Hom.:

13516

Cov.:

AF XY:

0.417

AC XY:

30982

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.314

Gnomad4 AMR

AF:

0.470

Gnomad4 ASJ

AF:

0.322

Gnomad4 EAS

AF:

0.561

Gnomad4 SAS

AF:

0.319

Gnomad4 FIN

AF:

0.471

Gnomad4 NFE

AF:

0.457

Gnomad4 OTH

AF:

0.397

Alfa

AF:

0.430

Hom.:

6773

Bravo

AF:

0.415

Asia WGS

AF:

0.430

AC:

1493

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GABRA2-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.022

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over