rs12324292

Variant names:

• chr15-26757934-C-T
• rs12324292
• NM_000814.6:c.240+14468G>A

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+14468G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,008 control chromosomes in the GnomAD database, including 9,141 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 0.34 (9141 hom., cov: 32)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• Publications: 6 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

LOC112268151 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.436 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.240+14468G>A		intron	N/A	NP_000805.1
	GABRB3	NM_021912.5		c.240+14468G>A		intron	N/A	NP_068712.1
	GABRB3	NM_001278631.2		c.-112+14468G>A		intron	N/A	NP_001265560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.240+14468G>A		intron	N/A	ENSP00000308725.5
	GABRB3	ENST00000541819.6	TSL:1	c.408+14468G>A		intron	N/A	ENSP00000442408.2
	GABRB3	ENST00000299267.9	TSL:1	c.240+14468G>A		intron	N/A	ENSP00000299267.4

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51101 AN: 151890 Hom.: 9115 Cov.: 32

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.337 AC: 51169 AN: 152008 Hom.: 9141 Cov.: 32 AF XY: 0.334 AC XY: 24849 AN XY: 74320

African (AFR) AF: 0.441 AC: 18296 AN: 41454

American (AMR) AF: 0.234 AC: 3571 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3468

East Asian (EAS) AF: 0.127 AC: 659 AN: 5176

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4816

European-Finnish (FIN) AF: 0.368 AC: 3872 AN: 10524

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21338 AN: 67974

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.313 Hom.: 13321

Bravo AF: 0.329

Asia WGS AF: 0.191 AC: 660 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.6
DANN	Benign	0.75
PhyloP100		0.098
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: rs12324292; hg19: chr15-27003081;