Genetic Variant GABRB2:p.Ala471Ser (chr5-161294209-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001371727.1(GABRB2):c.1411G>T(p.Ala471Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A471T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GABRB2
NM_001371727.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70

Publications

0 publications found

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]

GABRB2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 92
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19087479).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371727.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRB2	NM_001371727.1	MANE Select	c.1411G>T	p.Ala471Ser	missense	Exon 10 of 10	NP_001358656.1	P47870-2
GABRB2	NM_021911.3		c.1411G>T	p.Ala471Ser	missense	Exon 11 of 11	NP_068711.1	P47870-2
GABRB2	NM_000813.3		c.1297G>T	p.Ala433Ser	missense	Exon 10 of 10	NP_000804.1	P47870-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRB2	ENST00000393959.6	TSL:1 MANE Select	c.1411G>T	p.Ala471Ser	missense	Exon 10 of 10	ENSP00000377531.1	P47870-2
GABRB2	ENST00000353437.10	TSL:1	c.1297G>T	p.Ala433Ser	missense	Exon 10 of 10	ENSP00000274546.6	P47870-1
GABRB2	ENST00000520240.5	TSL:1	c.1297G>T	p.Ala433Ser	missense	Exon 10 of 10	ENSP00000429320.1	P47870-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.0043

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

-0.0072

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.019

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.1

PhyloP100

4.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.82

REVEL

Uncertain

0.30

Sift

Benign

0.39

Sift4G

Benign

0.51

Polyphen

0.013

Vest4

0.17

MutPred

0.46

Gain of phosphorylation at A471 (P = 0.006)

MVP

0.63

MPC

0.37

ClinPred

0.45

GERP RS

5.7

Varity_R

0.12

gMVP

0.57

Mutation Taster

=47/53

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over