chr4-46250469-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000807.4(GABRA2):ā€‹c.1195A>Cā€‹(p.Lys399Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

GABRA2
NM_000807.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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=0.11122811).
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GABRA2NM_000807.4 linkuse as main transcriptc.1195A>C p.Lys399Gln missense_variant 10/10 ENST00000381620.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GABRA2ENST00000381620.9 linkuse as main transcriptc.1195A>C p.Lys399Gln missense_variant 10/101 NM_000807.4 P2P47869-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250700
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135454
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:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460484
Hom.:
0
Cov.:
31
AF XY:
0.00000826
AC XY:
6
AN XY:
726576
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:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 24, 2023The c.1195A>C (p.K399Q) alteration is located in exon 9 (coding exon 9) of the GABRA2 gene. This alteration results from a A to C substitution at nucleotide position 1195, causing the lysine (K) at amino acid position 399 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
23
DANN
Benign
0.86
DEOGEN2
Benign
0.12
T;T;T;T;T;T
Eigen
Benign
0.054
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.78
.;.;.;T;T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.11
T;T;T;T;T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
1.9
L;L;L;L;.;.
MutationTaster
Benign
0.60
N;N;N;N;N;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.31
N;N;N;N;.;N
REVEL
Uncertain
0.32
Sift
Benign
0.53
T;T;T;T;.;T
Sift4G
Benign
0.60
T;T;T;T;T;T
Polyphen
0.012
B;B;B;B;.;.
Vest4
0.11
MutPred
0.40
Loss of methylation at K399 (P = 0.0023);Loss of methylation at K399 (P = 0.0023);Loss of methylation at K399 (P = 0.0023);Loss of methylation at K399 (P = 0.0023);.;.;
MVP
0.78
MPC
0.28
ClinPred
0.18
T
GERP RS
6.0
Varity_R
0.10
gMVP
0.43

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.

Other links and lift over

dbSNP: rs747890495; hg19: chr4-46252486; API