rs587777309
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_001127644.2(GABRA1):c.917A>C(p.Lys306Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
GABRA1
NM_001127644.2 missense
NM_001127644.2 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 9.21
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001127644.2
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GABRA1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.924
PP5
?
Variant 5-161895726-A-C is Pathogenic according to our data. Variant chr5-161895726-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 127075.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-161895726-A-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRA1 | NM_001127644.2 | c.917A>C | p.Lys306Thr | missense_variant | 9/10 | ENST00000393943.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRA1 | ENST00000393943.10 | c.917A>C | p.Lys306Thr | missense_variant | 9/10 | 1 | NM_001127644.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 19 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 08, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;D;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M;M;M;M;.;M;M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;D;D;D;D;.;D;D
Vest4
0.94, 0.88, 0.94, 0.94
MutPred
Loss of methylation at K306 (P = 0.004);Loss of methylation at K306 (P = 0.004);Loss of methylation at K306 (P = 0.004);Loss of methylation at K306 (P = 0.004);Loss of methylation at K306 (P = 0.004);Loss of methylation at K306 (P = 0.004);.;Loss of methylation at K306 (P = 0.004);Loss of methylation at K306 (P = 0.004);
MVP
0.95
MPC
3.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at