4-47425856-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000812.4(GABRB1):c.1263C>G(p.His421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,120 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H421H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 5 hom. )

Consequence

GABRB1
NM_000812.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0530

Publications

8 publications found

Variant links:

Genes affected

GABRB1 (HGNC:4081): (gamma-aminobutyric acid type A receptor subunit beta1) 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 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]

GABRB1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 45
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GABRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011458993).

BP6

Variant 4-47425856-C-G is Benign according to our data. Variant chr4-47425856-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB1	NM_000812.4 link	c.1263C>G	p.His421Gln	missense_variant	Exon 9 of 9	ENST00000295454.8	NP_000803.2	P18505-1X5DNL6
GABRB1	XM_024453976.2 link	c.1164C>G	p.His388Gln	missense_variant	Exon 9 of 9		XP_024309744.1
GABRB1	XM_024453977.2 link	c.1164C>G	p.His388Gln	missense_variant	Exon 10 of 10		XP_024309745.1
GABRB1	XM_017007985.2 link	c.612C>G	p.His204Gln	missense_variant	Exon 5 of 5		XP_016863474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB1	ENST00000295454.8 link	c.1263C>G	p.His421Gln	missense_variant	Exon 9 of 9	1	NM_000812.4	ENSP00000295454.3		P18505-1

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

328

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00367

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00249

AC:

623

AN:

250638

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00412

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00307

AC:

4486

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2178

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.00154

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00101

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00357

AC:

3971

AN:

1111984

Other (OTH)

AF:

0.00382

AC:

231

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

273

546

818

1091

1364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00215

AC:

328

AN:

152344

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41576

American (AMR)

AF:

0.00183

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00367

AC:

250

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00304

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00260

AC:

316

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GABRB1: BS1, BS2 -

Jun 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GABRB1-related disorder

Benign:1

Mar 31, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.28

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.53

M_CAP

Benign

0.037

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

PhyloP100

-0.053

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.9

REVEL

Benign

0.13

Sift

Benign

0.16

Sift4G

Benign

0.17

Polyphen

0.0020

Vest4

0.36

MutPred

0.15

Gain of solvent accessibility (P = 0.0021);

MVP

0.68

MPC

0.51

ClinPred

0.0050

GERP RS

0.39

Varity_R

0.060

gMVP

0.80

Mutation Taster

=94/6

polymorphism

(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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4-47425856-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over