chr5-161294089-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001371727.1(GABRB2):​c.1531G>A​(p.Val511Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GABRB2
NM_001371727.1 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.04
Variant links:
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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GABRB2NM_001371727.1 linkuse as main transcriptc.1531G>A p.Val511Met missense_variant 10/10 ENST00000393959.6
GABRB2NM_021911.3 linkuse as main transcriptc.1531G>A p.Val511Met missense_variant 11/11
GABRB2NM_000813.3 linkuse as main transcriptc.1417G>A p.Val473Met missense_variant 10/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GABRB2ENST00000393959.6 linkuse as main transcriptc.1531G>A p.Val511Met missense_variant 10/101 NM_001371727.1 P47870-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 26, 2022In 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. ClinVar contains an entry for this variant (Variation ID: 1389252). This variant has not been reported in the literature in individuals affected with GABRB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 511 of the GABRB2 protein (p.Val511Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T;.;T;.;T
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
.;D;.;D;D;D
M_CAP
Benign
0.052
D
MetaRNN
Uncertain
0.46
T;T;T;T;T;T
MetaSVM
Uncertain
-0.011
T
MutationAssessor
Benign
1.9
L;L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.3
N;N;N;N;N;N
REVEL
Uncertain
0.45
Sift
Benign
0.10
T;T;T;T;T;T
Sift4G
Benign
0.12
T;T;T;T;T;T
Polyphen
0.14
B;B;P;B;P;P
Vest4
0.56
MutPred
0.47
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;
MVP
0.74
MPC
0.39
ClinPred
0.77
D
GERP RS
4.9
Varity_R
0.18
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77133486; hg19: chr5-160721096; API