rs1312439667
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The ENST00000393943.10(GABRA1):c.1351G>A(p.Ala451Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 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
GABRA1
ENST00000393943.10 missense
ENST00000393943.10 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 7.56
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.21481463).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GABRA1 | NM_001127644.2 | c.1351G>A | p.Ala451Thr | missense_variant | 10/10 | ENST00000393943.10 | NP_001121116.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GABRA1 | ENST00000393943.10 | c.1351G>A | p.Ala451Thr | missense_variant | 10/10 | 1 | NM_001127644.2 | ENSP00000377517 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251000Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135726
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727178
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2019 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GABRA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 451 of the GABRA1 protein (p.Ala451Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T;T;.;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;.;.;.;.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;N;N;N;.;N;N
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
.;N;N;N;N;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
.;D;D;D;D;.;.;.;.
Sift4G
Benign
.;T;T;T;T;.;.;.;.
Polyphen
B;B;B;B;B;B;.;B;B
Vest4
0.14, 0.12, 0.13, 0.13
MutPred
Gain of glycosylation at A451 (P = 0.0051);Gain of glycosylation at A451 (P = 0.0051);Gain of glycosylation at A451 (P = 0.0051);Gain of glycosylation at A451 (P = 0.0051);Gain of glycosylation at A451 (P = 0.0051);Gain of glycosylation at A451 (P = 0.0051);.;Gain of glycosylation at A451 (P = 0.0051);Gain of glycosylation at A451 (P = 0.0051);
MVP
0.53
MPC
0.37
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at