chr5-161294271-C-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001371727.1(GABRB2):āc.1349G>Cā(p.Ser450Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000016 ( 0 hom. )
Consequence
GABRB2
NM_001371727.1 missense
NM_001371727.1 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 3.93
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. GenCC has associacion of the gene with undetermined early-onset epileptic encephalopathy, epileptic encephalopathy, infantile or early childhood, 2.
BP4
Computational evidence support a benign effect (MetaRNN=0.103753924).
BS2
High AC in GnomAdExome4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GABRB2 | NM_001371727.1 | c.1349G>C | p.Ser450Thr | missense_variant | 10/10 | ENST00000393959.6 | NP_001358656.1 | |
GABRB2 | NM_021911.3 | c.1349G>C | p.Ser450Thr | missense_variant | 11/11 | NP_068711.1 | ||
GABRB2 | NM_000813.3 | c.1235G>C | p.Ser412Thr | missense_variant | 10/10 | NP_000804.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251324Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135816
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461846Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15AN XY: 727224
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
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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 | Labcorp Genetics (formerly Invitae), Labcorp | Jun 16, 2020 | 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 serine with threonine at codon 450 of the GABRB2 protein (p.Ser450Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;.;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
B;B;B;B;B;B
Vest4
MutPred
Loss of disorder (P = 0.0676);Loss of disorder (P = 0.0676);.;.;.;.;
MVP
MPC
0.29
ClinPred
T
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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