rs797045045

chr15-26567721-C-Gchr15-26567721-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000814.6(GABRB3):c.695G>C(p.Arg232Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GABRB3 NM_000814.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 13 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-26567721-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GABRB3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 15-26567721-C-G is Pathogenic according to our data. Variant chr15-26567721-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209156.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRB3	NM_000814.6	c.695G>C	p.Arg232Pro	missense_variant	7/9	ENST00000311550.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRB3	ENST00000311550.10	c.695G>C	p.Arg232Pro	missense_variant	7/9	1	NM_000814.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 14, 2014

Likely pathogenicity based on finding it once in our laboratory de novo in a 20-year-old female with intellectual disability and seizure disorder -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;.;D;D
Polyphen		1.0	.;D;.;D;D;.;.;.;.
Vest4		0.91
MutPred		0.75		.;.;.;Loss of MoRF binding (P = 0.014);.;.;.;.;.;
MVP		0.98
MPC		2.8
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.99
gMVP		1.0

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: rs797045045; hg19: chr15-26812868;