Genetic Variant NM_000812.4:c.157C>T (chr4-47031990-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000812.4(GABRB1):c.157C>T(p.Arg53Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Consequence

GABRB1
NM_000812.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.790

Publications

2 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:

ENSG00000301858 (HGNC:):

ENSG00000301858 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 4-47031990-C-T is Pathogenic according to our data. Variant chr4-47031990-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 431076.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000812.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB1	NM_000812.4	MANE Select	c.157C>T	p.Arg53Trp	missense	Exon 2 of 9	NP_000803.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GABRB1	ENST00000295454.8	TSL:1 MANE Select	c.157C>T	p.Arg53Trp	missense	Exon 2 of 9	ENSP00000295454.3
GABRB1	ENST00000509366.5	TSL:1	n.258C>T		non_coding_transcript_exon	Exon 2 of 4
GABRB1	ENST00000513567.5	TSL:4	c.58C>T	p.Arg20Trp	missense	Exon 2 of 4	ENSP00000426753.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 45

Pathogenic:1

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.71

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.9

PhyloP100

0.79

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.82

MutPred

0.97

Loss of disorder (P = 0.0627)

MVP

0.91

MPC

2.6

ClinPred

1.0

GERP RS

3.3

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.79

gMVP

0.92

Mutation Taster

=78/22

disease causing (ClinVar)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over