chr15-26773694-G-C

Variant names:

• chr15-26773694-G-C
• ENST00000299267.9:c.31C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_021912.5(GABRB3):​c.31C>G​(p.Pro11Ala) 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 benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABRB3 NM_021912.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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 1 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: 4.3655 (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=0.12531924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_021912.5	c.31C>G	p.Pro11Ala	missense_variant	Exon 1 of 9		NP_068712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000299267.9	c.31C>G	p.Pro11Ala	missense_variant	Exon 1 of 9	1		ENSP00000299267.4
GABRB3	ENST00000541819.6	c.249-922C>G		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000638099.1	c.-20+249C>G		intron_variant	Intron 1 of 8	5		ENSP00000490678.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.90
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Polyphen		0.033	B
Vest4		0.33
MutPred		0.64		Gain of helix (P = 0.027);
MVP		0.79
ClinPred		0.075	T
GERP RS		2.2

Splicing

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: chr15-27018841;