15-26774814-C-T

Variant names:

• chr15-26774814-C-T
• rs4243768
• ENST00000541819.6:c.249-2042G>A

Variant summary

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

The ENST00000541819.6(GABRB3):​c.249-2042G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.89 in 152,256 control chromosomes in the GnomAD database, including 60,789 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 0.89 (60789 hom., cov: 34)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.249-2042G>A		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000557641.5	n.453-2042G>A		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135473 AN: 152140 Hom.: 60751 Cov.: 34

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.983

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.898

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

GnomAD4 genome AF: 0.890 AC: 135568 AN: 152256 Hom.: 60789 Cov.: 34 AF XY: 0.894 AC XY: 66534 AN XY: 74428

African (AFR) AF: 0.768 AC: 31855 AN: 41504

American (AMR) AF: 0.927 AC: 14195 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3299 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5172 AN: 5180

South Asian (SAS) AF: 0.983 AC: 4748 AN: 4830

European-Finnish (FIN) AF: 0.943 AC: 10000 AN: 10604

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63403 AN: 68040

Other (OTH) AF: 0.899 AC: 1903 AN: 2116

Alfa AF: 0.912 Hom.: 21045

Bravo AF: 0.882

Asia WGS AF: 0.973 AC: 3383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.16
PhyloP100		-0.39
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: rs4243768; hg19: chr15-27019961;