Variant chr4-46250458-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2PP2BP4_ModerateBS2

The NM_000807.4(GABRA2):c.1206C>G(p.Asn402Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GABRA2
NM_000807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, GABRA2

BP4

Computational evidence support a benign effect (MetaRNN=0.07077196).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4 linkuse as main transcript	c.1206C>G	p.Asn402Lys	missense_variant	10/10	ENST00000381620.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA2	ENST00000381620.9 linkuse as main transcript	c.1206C>G	p.Asn402Lys	missense_variant	10/10	1	NM_000807.4	P2	P47869-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250630

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460408

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 462 of the GABRA2 protein (p.Asn462Lys). This variant is present in population databases (rs749211070, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GABRA2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.14

T;T;T;T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.87

M_CAP

Benign

0.033

MetaRNN

Benign

0.071

T;T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.34

N;N;N;N;.;.

MutationTaster

Benign

0.63

N;N;N;N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.87

T;T;T;T;T;T

Sift4G

Benign

0.93

T;T;T;T;T;T

Polyphen

0.0050

B;B;B;B;.;.

Vest4

0.17

MutPred

0.37

Gain of methylation at N402 (P = 0.0038);Gain of methylation at N402 (P = 0.0038);Gain of methylation at N402 (P = 0.0038);Gain of methylation at N402 (P = 0.0038);.;.;

MVP

0.75

MPC

0.29

ClinPred

0.12

GERP RS

3.1

Varity_R

0.16

gMVP

0.16

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