15-26547831-G-C

Variant names:

• chr15-26547831-G-C
• NM_000814.6:c.1384C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000814.6(GABRB3):​c.1384C>G​(p.Leu462Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB3 NM_000814.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

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]

ACMG classification

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	c.1384C>G	p.Leu462Val	missense_variant	Exon 9 of 9	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.1384C>G	p.Leu462Val	missense_variant	Exon 9 of 9	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Uncertain:1

Dec 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 462 of the GABRB3 protein (p.Leu462Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GABRB3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GABRB3 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;.;.;.;.;.;.;.
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D;D;D;.;D;D;.
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.0	.;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.87	.;N;.;N;N;.;.;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.20	.;T;.;T;T;.;.;T;T
Sift4G	Benign	0.28	T;T;T;T;T;.;.;T;T
Polyphen		0.089, 0.16, 0.035	.;B;.;B;B;.;.;.;.
Vest4		0.42
MutPred		0.61		.;.;.;Loss of stability (P = 0.0871);.;.;.;.;.;
MVP		0.78
MPC		2.0
ClinPred		0.53	D
GERP RS		6.0
Varity_R		0.27
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-26792978;