Genetic Variant NM_000814.6:c.94G>T (chr15-26772759-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

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

The NM_000814.6(GABRB3):c.94G>T(p.Gly32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,980 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GABRB3
NM_000814.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50

Variant links:

Genes affected

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 links:

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 the GABRB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.3856 (above the threshold of 3.09). Trascript score misZ: 4.4544 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, developmental and epileptic encephalopathy, 43, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, epilepsy, childhood absence, susceptibility to, 5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6 link	c.94G>T	p.Gly32Trp	missense_variant	Exon 2 of 9	ENST00000311550.10	NP_000805.1	P28472-1
GABRB3	NM_001278631.2 link	c.-258G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 10		NP_001265560.1	P28472-4
GABRB3	NM_021912.5 link	c.94G>T	p.Gly32Trp	missense_variant	Exon 2 of 9		NP_068712.1	P28472-2B2RCW8X5DQY4
GABRB3	NM_001278631.2 link	c.-258G>T		5_prime_UTR_variant	Exon 2 of 10		NP_001265560.1	P28472-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10 link	c.94G>T	p.Gly32Trp	missense_variant	Exon 2 of 9	1	NM_000814.6	ENSP00000308725.5		P28472-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1388980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.33e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

0.087

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Uncertain

0.058

MutationAssessor

Benign

1.5

L;.;L

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.6

N;N;N

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.22

B;D;D

Vest4

0.46

MutPred

0.53

.;Loss of disorder (P = 0.0112);.;

MVP

0.84

MPC

2.6

ClinPred

0.94

GERP RS

3.8

Varity_R

0.25

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over