chr15-26799458-A-C

Variant names:

• chr15-26799458-A-C
• rs6576618
• ENST00000541819.6:c.248+16909T>G

Variant summary

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

The ENST00000541819.6(GABRB3):​c.248+16909T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 150,926 control chromosomes in the GnomAD database, including 27,564 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 0.60 (27564 hom., cov: 28)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 2 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=-1.05).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 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.248+16909T>G		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000637226.1	n.13-3366T>G		intron_variant	Intron 1 of 1	5
GABRB3	ENST00000637893.1	n.41-1012T>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90275 AN: 150828 Hom.: 27544 Cov.: 28

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.608

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

GnomAD4 genome AF: 0.598 AC: 90321 AN: 150926 Hom.: 27564 Cov.: 28 AF XY: 0.605 AC XY: 44576 AN XY: 73674

African (AFR) AF: 0.523 AC: 21520 AN: 41126

American (AMR) AF: 0.709 AC: 10717 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2145 AN: 3458

East Asian (EAS) AF: 0.870 AC: 4455 AN: 5118

South Asian (SAS) AF: 0.709 AC: 3385 AN: 4776

European-Finnish (FIN) AF: 0.572 AC: 5868 AN: 10252

Middle Eastern (MID) AF: 0.549 AC: 157 AN: 286

European-Non Finnish (NFE) AF: 0.595 AC: 40352 AN: 67816

Other (OTH) AF: 0.610 AC: 1262 AN: 2068

Alfa AF: 0.593 Hom.: 36141

Bravo AF: 0.605

Asia WGS AF: 0.795 AC: 2767 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.85
DANN	Benign	0.21
PhyloP100		-1.7
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: rs6576618; hg19: chr15-27044605;