Genetic Variant GABRA2:p.Lys132Lys (chr4-46312576-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000807.4(GABRA2):c.396A>G(p.Lys132Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,595,942 control chromosomes in the GnomAD database, including 145,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11580 hom., cov: 32)

Exomes 𝑓: 0.43 ( 133934 hom. )

Consequence

GABRA2
NM_000807.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.110

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 4-46312576-T-C is Benign according to our data. Variant chr4-46312576-T-C is described in ClinVar as [Benign]. Clinvar id is 1168077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.11 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4 link	c.396A>G	p.Lys132Lys	synonymous_variant	Exon 5 of 10	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.396A>G	p.Lys132Lys	synonymous_variant	Exon 5 of 10	1	NM_000807.4	ENSP00000371033.4		P47869-1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57479

AN:

151908

Hom.:

11565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.382

Gnomad AMR

AF:

0.449

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.524

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.373

GnomAD3 exomes

AF:

0.404

AC:

95718

AN:

237012

Hom.:

20498

AF XY:

0.397

AC XY:

50804

AN XY:

128098

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.504

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.518

Gnomad SAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.416

Gnomad NFE exome

AF:

0.427

Gnomad OTH exome

AF:

0.404

GnomAD4 exome

AF:

0.425

AC:

613714

AN:

1443916

Hom.:

133934

Cov.:

AF XY:

0.419

AC XY:

300932

AN XY:

718114

show subpopulations

Gnomad4 AFR exome

AF:

0.239

Gnomad4 AMR exome

AF:

0.492

Gnomad4 ASJ exome

AF:

0.313

Gnomad4 EAS exome

AF:

0.486

Gnomad4 SAS exome

AF:

0.242

Gnomad4 FIN exome

AF:

0.418

Gnomad4 NFE exome

AF:

0.444

Gnomad4 OTH exome

AF:

0.411

GnomAD4 genome

AF:

0.378

AC:

57511

AN:

152026

Hom.:

11580

Cov.:

AF XY:

0.379

AC XY:

28136

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.252

Gnomad4 AMR

AF:

0.449

Gnomad4 ASJ

AF:

0.305

Gnomad4 EAS

AF:

0.524

Gnomad4 SAS

AF:

0.241

Gnomad4 FIN

AF:

0.415

Gnomad4 NFE

AF:

0.436

Gnomad4 OTH

AF:

0.372

Alfa

AF:

0.398

Hom.:

5931

Bravo

AF:

0.383

Asia WGS

AF:

0.368

AC:

1279

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-0.55

CADD

Benign

5.7

DANN

Benign

0.63

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

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