chr5-161294145-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_001371727.1(GABRB2):c.1475G>A(p.Arg492His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GABRB2
NM_001371727.1 missense
NM_001371727.1 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.80
Genes affected
GABRB2 (HGNC:4082): (gamma-aminobutyric acid type A receptor subunit beta2) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 2 subunit. It is mapped to chromosome 5q34 in a cluster comprised of genes encoding alpha 1 and gamma 2 subunits of the GABA A receptor. Alternative splicing of this gene generates 2 transcript variants, differing by a 114 bp insertion. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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), GABRB2. . Gene score misZ 3.3968 (greater than the threshold 3.09). Trascript score misZ 4.0905 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, epileptic encephalopathy, infantile or early childhood, 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABRB2 | NM_001371727.1 | c.1475G>A | p.Arg492His | missense_variant | 10/10 | ENST00000393959.6 | |
GABRB2 | NM_021911.3 | c.1475G>A | p.Arg492His | missense_variant | 11/11 | ||
GABRB2 | NM_000813.3 | c.1361G>A | p.Arg454His | missense_variant | 10/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABRB2 | ENST00000393959.6 | c.1475G>A | p.Arg492His | missense_variant | 10/10 | 1 | NM_001371727.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461798Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727196
GnomAD4 exome
AF:
AC:
2
AN:
1461798
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
727196
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 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 disruptive, 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 GABRB2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 492 of the GABRB2 protein (p.Arg492His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;D;D;D;D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0627);Loss of MoRF binding (P = 0.0627);.;.;.;.;
MVP
MPC
1.2
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