Variant rs1554084012 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001127644.2(GABRA1):c.187G>A(p.Glu63Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GABRA1
NM_001127644.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

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:

GABRA1 (HGNC:):

GABRA1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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), GABRA1. . Gene score misZ 3.1498 (greater than the threshold 3.09). Trascript score misZ 4.2662 (greater than threshold 3.09). GenCC has associacion of gene with juvenile myoclonic epilepsy, developmental and epileptic encephalopathy, 19, epilepsy, idiopathic generalized, susceptibility to, 13, Dravet syndrome, developmental and epileptic encephalopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA1	NM_001127644.2 linkuse as main transcript	c.187G>A	p.Glu63Lys	missense_variant, splice_region_variant	3/10	ENST00000393943.10	NP_001121116.1	P14867

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10 linkuse as main transcript	c.187G>A	p.Glu63Lys	missense_variant, splice_region_variant	3/10	1	NM_001127644.2	ENSP00000377517.4		P14867

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.44e-7

AC:

AN:

1344864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

675522

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:

9.95e-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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;.;.;.;.;D;.;D;D;.;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.8

L;L;L;L;L;.;L;.;.;L;.;.;L

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.41

Sift

Benign

0.46

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

Sift4G

Benign

0.48

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

Polyphen

0.66

P;P;P;P;P;.;P;.;.;P;.;.;P

Vest4

0.78, 0.76

MutPred

0.56

Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);.;Gain of methylation at E63 (P = 0.014);.;Gain of methylation at E63 (P = 0.014);Gain of methylation at E63 (P = 0.014);

MVP

0.84

MPC

1.5

ClinPred

0.94

GERP RS

5.5

Varity_R

0.41

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.010

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