Variant chr4-46250456-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000807.4(GABRA2):c.1208A>T(p.Lys403Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GABRA2
NM_000807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.13

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRA2. . Gene score misZ 3.1277 (greater than the threshold 3.09). Trascript score misZ 3.4041 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 78, undetermined early-onset epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.36402673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA2	NM_000807.4 linkuse as main transcript	c.1208A>T	p.Lys403Met	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.1208A>T	p.Lys403Met	missense_variant	10/10	1	NM_000807.4	P2	P47869-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460368

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726518

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2022

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. This variant has not been reported in the literature in individuals affected with GABRA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 463 of the GABRA2 protein (p.Lys463Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;T;T;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

.;.;.;D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.36

T;T;T;T;T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.6

M;M;M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.1

N;N;N;N;.;N

REVEL

Uncertain

0.58

Sift

Benign

0.054

T;T;T;T;.;D

Sift4G

Uncertain

0.028

D;D;D;D;D;D

Polyphen

0.91

P;P;P;P;.;.

Vest4

0.38

MutPred

0.50

Loss of methylation at K403 (P = 0.0153);Loss of methylation at K403 (P = 0.0153);Loss of methylation at K403 (P = 0.0153);Loss of methylation at K403 (P = 0.0153);.;.;

MVP

0.64

MPC

0.95

ClinPred

0.90

GERP RS

6.0

Varity_R

0.18

gMVP

0.67

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over