15-26773893-C-G

Variant names:

• chr15-26773893-C-G
• rs4906901
• ENST00000541819.6:c.249-1121G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000541819.6(GABRB3):​c.249-1121G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 463,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 24)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_021912.5	c.-169G>C		upstream_gene_variant			NP_068712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000541819.6	c.249-1121G>C		intron_variant	Intron 2 of 9	1		ENSP00000442408.2
GABRB3	ENST00000638099.1	c.-20+50G>C		intron_variant	Intron 1 of 8	5		ENSP00000490678.1
GABRB3	ENST00000557641.5	n.453-1121G>C		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000216 AC: 1 AN: 463230 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 243340

African (AFR) AF: 0.00 AC: 0 AN: 11956

American (AMR) AF: 0.00 AC: 0 AN: 18642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13464

East Asian (EAS) AF: 0.00 AC: 0 AN: 30364

South Asian (SAS) AF: 0.00 AC: 0 AN: 45272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1954

European-Non Finnish (NFE) AF: 0.00000362 AC: 1 AN: 276210

Other (OTH) AF: 0.00 AC: 0 AN: 25980

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.18
PhyloP100		-0.27
PromoterAI		0.021	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4906901; hg19: chr15-27019040;