15-26581134-C-G

Variant names:

• chr15-26581134-C-G
• rs12440905
• NM_000814.6:c.545-678G>C

Variant summary

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

The NM_000814.6(GABRB3):​c.545-678G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 161,088 control chromosomes in the GnomAD database, including 66,142 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 (61867 hom., cov: 31)
  • Exomes 𝑓: 0.98 (4275 hom.)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.545-678G>C		intron_variant	Intron 5 of 8	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.545-678G>C		intron_variant	Intron 5 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.891 AC: 135413 AN: 152040 Hom.: 61837 Cov.: 31

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.964

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.917

GnomAD4 exome AF: 0.977 AC: 8729 AN: 8930 Hom.: 4275 Cov.: 0 AF XY: 0.979 AC XY: 4564 AN XY: 4664

African (AFR) AF: 0.482 AC: 27 AN: 56

American (AMR) AF: 0.964 AC: 2272 AN: 2356

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 45 AN: 48

East Asian (EAS) AF: 0.966 AC: 545 AN: 564

South Asian (SAS) AF: 0.995 AC: 1104 AN: 1110

European-Finnish (FIN) AF: 0.963 AC: 52 AN: 54

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.989 AC: 4397 AN: 4444

Other (OTH) AF: 0.963 AC: 283 AN: 294

GnomAD4 genome AF: 0.890 AC: 135489 AN: 152158 Hom.: 61867 Cov.: 31 AF XY: 0.894 AC XY: 66556 AN XY: 74408

African (AFR) AF: 0.660 AC: 27371 AN: 41442

American (AMR) AF: 0.945 AC: 14456 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 3265 AN: 3472

East Asian (EAS) AF: 0.964 AC: 4967 AN: 5154

South Asian (SAS) AF: 0.985 AC: 4746 AN: 4820

European-Finnish (FIN) AF: 0.995 AC: 10563 AN: 10620

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 67006 AN: 68038

Other (OTH) AF: 0.918 AC: 1936 AN: 2110

Alfa AF: 0.939 Hom.: 3386

Bravo AF: 0.875

Asia WGS AF: 0.942 AC: 3277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.018
DANN	Benign	0.39
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs12440905; hg19: chr15-26826281;