15-26794935-T-G

Variant names:

• chr15-26794935-T-G
• rs4906908
• ENST00000541819.6:c.248+21432A>C

Variant summary

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

The ENST00000541819.6(GABRB3):​c.248+21432A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 152,060 control chromosomes in the GnomAD database, including 16,729 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 0.43 (16729 hom., cov: 32)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.66
• Publications: 11 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541819.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000541819.6	TSL:1	c.248+21432A>C		intron	N/A	ENSP00000442408.2	F5H7N0

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65303 AN: 151942 Hom.: 16720 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.430 AC: 65315 AN: 152060 Hom.: 16729 Cov.: 32 AF XY: 0.439 AC XY: 32601 AN XY: 74316

African (AFR) AF: 0.133 AC: 5542 AN: 41526

American (AMR) AF: 0.612 AC: 9355 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1978 AN: 3466

East Asian (EAS) AF: 0.587 AC: 3027 AN: 5156

South Asian (SAS) AF: 0.620 AC: 2992 AN: 4826

European-Finnish (FIN) AF: 0.507 AC: 5347 AN: 10550

Middle Eastern (MID) AF: 0.441 AC: 128 AN: 290

European-Non Finnish (NFE) AF: 0.524 AC: 35578 AN: 67950

Other (OTH) AF: 0.480 AC: 1011 AN: 2106

Alfa AF: 0.500 Hom.: 10161

Bravo AF: 0.423

Asia WGS AF: 0.621 AC: 2158 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.24
DANN	Benign	0.58
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4906908;

hg19: chr15-27040082;