NM_000814.6:c.175C>T

Variant names:

• chr15-26772467-G-A
• rs1555383878
• NM_000814.6:c.175C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000814.6(GABRB3):​c.175C>T​(p.Pro59Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GABRB3 NM_000814.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.61

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 Likely_benign. Variant got -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39559034).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.175C>T	p.Pro59Ser	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000311550.10	NP_000805.1
GABRB3	NM_021912.5	c.175C>T	p.Pro59Ser	missense_variant, splice_region_variant	Exon 3 of 9		NP_068712.1
GABRB3	NM_001278631.2	c.-177C>T		splice_region_variant	Exon 3 of 10		NP_001265560.1
GABRB3	NM_001278631.2	c.-177C>T		5_prime_UTR_variant	Exon 3 of 10		NP_001265560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.175C>T	p.Pro59Ser	missense_variant, splice_region_variant	Exon 3 of 9	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458070 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725330

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: 0.00000721

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 28, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P59S variant (also known as c.175C>T), located in coding exon 3 of the GABRB3 gene, results from a C to T substitution at nucleotide position 175. The proline at codon 59 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 59 of the GABRB3 protein (p.Pro59Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 34645491). ClinVar contains an entry for this variant (Variation ID: 469573). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	0.083
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.90	L;.;L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.93	N;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.074	T;T;D;.
Sift4G	Benign	0.26	T;T;T;.
Polyphen		0.0060	B;B;B;.
Vest4		0.090
MutPred		0.40		.;Loss of catalytic residue at P115 (P = 0.1268);.;.;
MVP		0.44
MPC		1.2
ClinPred		0.31	T
GERP RS		4.6
Varity_R		0.27
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs1555383878; hg19: chr15-27017614;