chr1-2029730-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000815.5(GABRD):āc.1027G>Cā(p.Ala343Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ). Synonymous variant affecting the same amino acid position (i.e. A343A) has been classified as Likely benign.
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Consequence
GABRD
NM_000815.5 missense
NM_000815.5 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 4.62
Genes affected
GABRD (HGNC:4084): (gamma-aminobutyric acid type A receptor subunit delta) Gamma-aminobutyric acid (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. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRD | NM_000815.5 | c.1027G>C | p.Ala343Pro | missense_variant | 8/9 | ENST00000378585.7 | |
GABRD | XM_017000936.2 | c.1732G>C | p.Ala578Pro | missense_variant | 7/8 | ||
GABRD | XM_011541194.4 | c.1066G>C | p.Ala356Pro | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRD | ENST00000378585.7 | c.1027G>C | p.Ala343Pro | missense_variant | 8/9 | 1 | NM_000815.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33
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GnomAD4 exome Cov.: 33
GnomAD4 exome
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33
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74380
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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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2017 | 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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GABRD-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 343 of the GABRD protein (p.Ala343Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;D;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.
REVEL
Uncertain
Sift
Benign
T;.;.;.;.
Sift4G
Benign
T;.;.;.;.
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of glycosylation at A343 (P = 0.0089);.;Gain of glycosylation at A343 (P = 0.0089);.;.;
MVP
MPC
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