rs8043440

Variant names:

• chr15-26727939-T-C
• rs8043440
• NM_000814.6:c.240+44463A>G

Variant summary

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

The NM_000814.6(GABRB3):​c.240+44463A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,158 control chromosomes in the GnomAD database, including 2,967 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 0.18 (2967 hom., cov: 32)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000814.6. 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
	GABRB3	NM_000814.6	MANE Select	c.240+44463A>G		intron	N/A	NP_000805.1	P28472-1
	GABRB3	NM_021912.5		c.240+44463A>G		intron	N/A	NP_068712.1	X5DQY4
	GABRB3	NM_001278631.2		c.-112+44463A>G		intron	N/A	NP_001265560.1	P28472-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.240+44463A>G		intron	N/A	ENSP00000308725.5	P28472-1
	GABRB3	ENST00000541819.6	TSL:1	c.408+44463A>G		intron	N/A	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000299267.9	TSL:1	c.240+44463A>G		intron	N/A	ENSP00000299267.4	P28472-2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27377 AN: 152040 Hom.: 2964 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.167

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

GnomAD4 genome AF: 0.180 AC: 27395 AN: 152158 Hom.: 2967 Cov.: 32 AF XY: 0.179 AC XY: 13335 AN XY: 74400

African (AFR) AF: 0.295 AC: 12253 AN: 41502

American (AMR) AF: 0.142 AC: 2167 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 853 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1596 AN: 5160

South Asian (SAS) AF: 0.152 AC: 730 AN: 4812

European-Finnish (FIN) AF: 0.108 AC: 1146 AN: 10604

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8068 AN: 68002

Other (OTH) AF: 0.164 AC: 347 AN: 2112

Alfa AF: 0.147 Hom.: 8055

Bravo AF: 0.190

Asia WGS AF: 0.220 AC: 766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.4
DANN	Benign	0.40
PhyloP100		-0.10
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: rs8043440; hg19: chr15-26973086;