rs12442889

Variant names:

• chr15-26671953-C-T
• rs12442889
• NM_000814.6:c.241-50419G>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.241-50419G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 151,888 control chromosomes in the GnomAD database, including 6,012 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 0.26 (6012 hom., cov: 33)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.241-50419G>A		intron_variant	Intron 3 of 8	ENST00000311550.10	NP_000805.1
GABRB3	NM_021912.5	c.241-50419G>A		intron_variant	Intron 3 of 8		NP_068712.1
GABRB3	NM_001191320.2	c.-16+44661G>A		intron_variant	Intron 1 of 6		NP_001178249.1
GABRB3	NM_001278631.2	c.-111-29425G>A		intron_variant	Intron 3 of 9		NP_001265560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.241-50419G>A		intron_variant	Intron 3 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39860 AN: 151772 Hom.: 6009 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.300

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

GnomAD4 genome AF: 0.263 AC: 39878 AN: 151888 Hom.: 6012 Cov.: 33 AF XY: 0.265 AC XY: 19634 AN XY: 74210

African (AFR) AF: 0.139 AC: 5755 AN: 41380

American (AMR) AF: 0.354 AC: 5398 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1394 AN: 3468

East Asian (EAS) AF: 0.112 AC: 575 AN: 5148

South Asian (SAS) AF: 0.283 AC: 1364 AN: 4818

European-Finnish (FIN) AF: 0.266 AC: 2802 AN: 10550

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21479 AN: 67944

Other (OTH) AF: 0.297 AC: 626 AN: 2110

Alfa AF: 0.284 Hom.: 1006

Bravo AF: 0.263

Asia WGS AF: 0.196 AC: 683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.66
PhyloP100		-0.12
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: rs12442889; hg19: chr15-26917100;