rs71651682

chr15-26772759-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000814.6(GABRB3):c.94G>A(p.Gly32Arg) 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. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GABRB3 NM_000814.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 1.50

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 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 219) in uniprot entity GBRB3_HUMAN there are 39 pathogenic changes around while only 7 benign (85%) in NM_000814.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABRB3
• BP4: Computational evidence support a benign effect (MetaRNN=0.29078913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB3	NM_000814.6	c.94G>A	p.Gly32Arg	missense_variant	2/9	ENST00000311550.10
GABRB3	NM_021912.5	c.94G>A	p.Gly32Arg	missense_variant	2/9
GABRB3	NM_001278631.2	c.-258G>A		5_prime_UTR_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB3	ENST00000311550.10	c.94G>A	p.Gly32Arg	missense_variant	2/9	1	NM_000814.6	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388980 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691072

Gnomad4 AFR exome AF: 0.0000352

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizure;C0557874:Global developmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 09, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 32 of the GABRB3 protein (p.Gly32Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of GABRB3-related conditions (PMID: 18514161; Invitae). ClinVar contains an entry for this variant (Variation ID: 16193). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GABRB3 function (PMID: 18514161, 22303015, 35383156). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2020

Published functional studies demonstrate a damaging effect as G32R caused gamma 2L receptors to have impaired gating and gamma 2 subunit surface expression was significantly reduced (Gurba et al., 2012; Shi et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in a family with epilepsy, but also seen in unaffected family members (Tanaka et al., 2008); This variant is associated with the following publications: (PMID: 23934645, 19717338, 29390378, 22303015, 31435640, 26950270, 22765836, 18514161, 20308251, 20352446, 22206818, 26645412, 30755392) -

Epilepsy, childhood absence, susceptibility to, 5 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.45	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.094	T;D;D
Sift4G	Benign	0.12	T;D;D
Polyphen		0.025	B;B;B
Vest4		0.24
MutPred		0.44		.;Gain of solvent accessibility (P = 0.019);.;
MVP		0.99
MPC		1.5
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.23
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs71651682; hg19: chr15-27017906;