rs769743354

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001127644.2(GABRA1):c.94C>A(p.Gln32Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000687 in 1,600,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

GABRA1
NM_001127644.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.80

Variant links:

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRA1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in the GABRA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.1498 (above the threshold of 3.09). Trascript score misZ: 4.2662 (above the threshold of 3.09). GenCC associations: The gene is linked to juvenile myoclonic epilepsy, developmental and epileptic encephalopathy, 19, epilepsy, idiopathic generalized, susceptibility to, 13, Dravet syndrome, developmental and epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.2953133).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2 link	c.94C>A	p.Gln32Lys	missense_variant	Exon 3 of 10	ENST00000393943.10	NP_001121116.1	P14867

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10 link	c.94C>A	p.Gln32Lys	missense_variant	Exon 3 of 10	1	NM_001127644.2	ENSP00000377517.4		P14867

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250478

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135406

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000690

AC:

AN:

1449270

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

721918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000817

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151476

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73964

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 07, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q32K variant (also known as c.94C>A), located in coding exon 2 of the GABRA1 gene, results from a C to A substitution at nucleotide position 94. The glutamine at codon 32 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13

Uncertain:1

Oct 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 32 of the GABRA1 protein (p.Gln32Lys). This variant is present in population databases (rs769743354, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of GABRA1-related conditions (PMID: 35937053). ClinVar contains an entry for this variant (Variation ID: 536749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GABRA1 protein function with a negative predictive value of 95%. 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

0.074

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.23

T;T;.;T;T;T;T;T;.;.;T;.;.;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.063

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;.;D;.;.;.;T;.;T;T;.;T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.69

N;N;.;N;N;N;.;N;.;.;N;.;.;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.42

.;N;.;N;N;N;N;.;.;.;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.35

.;T;.;T;T;T;T;.;.;.;.;.;.;.

Sift4G

Benign

0.75

.;T;D;T;T;T;T;.;.;.;.;T;T;.

Polyphen

0.026

B;B;.;B;B;B;.;B;.;.;B;.;.;B

Vest4

0.54, 0.61, 0.55, 0.54

MutPred

0.47

Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);.;Gain of ubiquitination at Q32 (P = 0.009);.;Gain of ubiquitination at Q32 (P = 0.009);Gain of ubiquitination at Q32 (P = 0.009);

MVP

0.99

MPC

1.4

ClinPred

0.29

GERP RS

5.5

Varity_R

0.13

gMVP

0.58

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