ENST00000541819.6:c.249-2389T>G

Variant names:

• chr15-26775161-A-C
• rs4273008
• ENST00000541819.6:c.249-2389T>G

Variant summary

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

The ENST00000541819.6(GABRB3):​c.249-2389T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 152,296 control chromosomes in the GnomAD database, including 63,421 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 0.91 (63421 hom., cov: 33)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328
• Publications: 4 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=-0.96).
• 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.249-2389T>G		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000557641.5	n.453-2389T>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.911 AC: 138700 AN: 152178 Hom.: 63379 Cov.: 33

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.933

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.913

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

GnomAD4 genome AF: 0.911 AC: 138800 AN: 152296 Hom.: 63421 Cov.: 33 AF XY: 0.914 AC XY: 68027 AN XY: 74466

African (AFR) AF: 0.841 AC: 34959 AN: 41548

American (AMR) AF: 0.934 AC: 14282 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3301 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5170 AN: 5178

South Asian (SAS) AF: 0.983 AC: 4748 AN: 4828

European-Finnish (FIN) AF: 0.943 AC: 10015 AN: 10620

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

European-Non Finnish (NFE) AF: 0.932 AC: 63401 AN: 68034

Other (OTH) AF: 0.913 AC: 1931 AN: 2114

Alfa AF: 0.894 Hom.: 22572

Bravo AF: 0.906

Asia WGS AF: 0.976 AC: 3396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.7
DANN	Benign	0.32
PhyloP100		-0.33
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: rs4273008; hg19: chr15-27020308;