rs193920932

Positions:

chr5-161336734-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_001371727.1(GABRB2):c.577C>T(p.Arg193Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,610,322 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: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GABRB2
NM_001371727.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.57

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 links:

GABRB2 (HGNC:):

GABRB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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). 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, 0.755

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRB2	NM_001371727.1 linkuse as main transcript	c.577C>T	p.Arg193Cys	missense_variant	6/10	ENST00000393959.6	NP_001358656.1
GABRB2	NM_021911.3 linkuse as main transcript	c.577C>T	p.Arg193Cys	missense_variant	7/11		NP_068711.1	P47870-2
GABRB2	NM_000813.3 linkuse as main transcript	c.577C>T	p.Arg193Cys	missense_variant	7/10		NP_000804.1	P47870-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB2	ENST00000393959.6 linkuse as main transcript	c.577C>T	p.Arg193Cys	missense_variant	6/10	1	NM_001371727.1	ENSP00000377531.1		P47870-2

Frequencies

GnomAD3 genomes

AF:

0.00000670

AC:

AN:

149270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461052

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000670

AC:

AN:

149270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 08, 2022

ACMG classification criteria: PM2, PP3 -

Malignant tumor of prostate

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

- -

Intellectual disability

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 161752). 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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 193 of the GABRB2 protein (p.Arg193Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;D;.;T;.;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;.;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.8

L;L;L;.;L;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.3

D;D;D;D;D;D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D;D;D;D;D;.

Sift4G

Uncertain

0.053

T;T;D;D;D;D;D

Polyphen

0.88

P;P;B;B;B;D;.

Vest4

0.69

MutPred

0.55

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);.;.;

MVP

0.88

MPC

2.0

ClinPred

0.99

GERP RS

5.6

Varity_R

0.43

gMVP

0.94

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over