rs8023959

Variant names:

• chr15-26649158-A-C
• rs8023959
• NM_000814.6:c.241-27624T>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.241-27624T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,212 control chromosomes in the GnomAD database, including 1,208 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 0.12 (1208 hom., cov: 33)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 3 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.196 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	NM_000814.6	MANE Select	c.241-27624T>G		intron	N/A	NP_000805.1
	GABRB3	NM_021912.5		c.241-27624T>G		intron	N/A	NP_068712.1
	GABRB3	NM_001191320.2		c.-15-27624T>G		intron	N/A	NP_001178249.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.241-27624T>G		intron	N/A	ENSP00000308725.5
	GABRB3	ENST00000541819.6	TSL:1	c.409-27624T>G		intron	N/A	ENSP00000442408.2
	GABRB3	ENST00000299267.9	TSL:1	c.241-27624T>G		intron	N/A	ENSP00000299267.4

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17963 AN: 152094 Hom.: 1208 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0710

Gnomad FIN AF: 0.0735

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0992

Gnomad OTH AF: 0.101

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

GnomAD4 genome AF: 0.118 AC: 17974 AN: 152212 Hom.: 1208 Cov.: 33 AF XY: 0.117 AC XY: 8744 AN XY: 74424

African (AFR) AF: 0.154 AC: 6387 AN: 41514

American (AMR) AF: 0.202 AC: 3082 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 266 AN: 3472

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5168

South Asian (SAS) AF: 0.0706 AC: 340 AN: 4814

European-Finnish (FIN) AF: 0.0735 AC: 780 AN: 10616

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0992 AC: 6745 AN: 68024

Other (OTH) AF: 0.0994 AC: 210 AN: 2112

Alfa AF: 0.109 Hom.: 353

Bravo AF: 0.130

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.8
DANN	Benign	0.58
PhyloP100		-0.25
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: rs8023959; hg19: chr15-26894305;