15-26818391-T-C

Variant names:

• chr15-26818391-T-C
• rs4412952
• ENST00000541819.6:c.201-1977A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000541819.6(GABRB3):​c.201-1977A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 150,914 control chromosomes in the GnomAD database, including 20,625 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (20625 hom., cov: 28)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.367
• Publications: 1 publications found

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]

GABRB3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• epilepsy, childhood absence, susceptibility to, 5

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000541819.6	c.201-1977A>G		intron_variant	Intron 1 of 9	1		ENSP00000442408.2

Frequencies

GnomAD3 genomes AF: 0.477 AC: 71974 AN: 150798 Hom.: 20627 Cov.: 28

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.479

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.477 AC: 71975 AN: 150914 Hom.: 20625 Cov.: 28 AF XY: 0.479 AC XY: 35294 AN XY: 73654

African (AFR) AF: 0.156 AC: 6413 AN: 41120

American (AMR) AF: 0.417 AC: 6313 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1921 AN: 3462

East Asian (EAS) AF: 0.544 AC: 2793 AN: 5130

South Asian (SAS) AF: 0.539 AC: 2568 AN: 4762

European-Finnish (FIN) AF: 0.686 AC: 7059 AN: 10288

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.637 AC: 43118 AN: 67742

Other (OTH) AF: 0.481 AC: 1003 AN: 2084

Alfa AF: 0.533 Hom.: 2929

Bravo AF: 0.443

Asia WGS AF: 0.471 AC: 1635 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.8
DANN	Benign	0.55
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4412952; hg19: chr15-27063538;