15-26593258-A-T

Variant names:

• chr15-26593258-A-T
• rs12437672
• NM_000814.6:c.462-9844T>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.462-9844T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,120 control chromosomes in the GnomAD database, including 7,595 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 0.28 (7595 hom., cov: 32)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.618
• Publications: 5 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.808 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.462-9844T>A		intron	N/A	NP_000805.1
	GABRB3	NM_021912.5		c.462-9844T>A		intron	N/A	NP_068712.1
	GABRB3	NM_001191321.3		c.249-9844T>A		intron	N/A	NP_001178250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.462-9844T>A		intron	N/A	ENSP00000308725.5
	GABRB3	ENST00000541819.6	TSL:1	c.630-9844T>A		intron	N/A	ENSP00000442408.2
	GABRB3	ENST00000299267.9	TSL:1	c.462-9844T>A		intron	N/A	ENSP00000299267.4

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42345 AN: 152002 Hom.: 7584 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.279 AC: 42374 AN: 152120 Hom.: 7595 Cov.: 32 AF XY: 0.288 AC XY: 21379 AN XY: 74346

African (AFR) AF: 0.103 AC: 4272 AN: 41530

American (AMR) AF: 0.309 AC: 4717 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3470

East Asian (EAS) AF: 0.829 AC: 4284 AN: 5170

South Asian (SAS) AF: 0.418 AC: 2016 AN: 4818

European-Finnish (FIN) AF: 0.365 AC: 3857 AN: 10554

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.311 AC: 21126 AN: 67978

Other (OTH) AF: 0.258 AC: 545 AN: 2112

Alfa AF: 0.282 Hom.: 849

Bravo AF: 0.266

Asia WGS AF: 0.553 AC: 1922 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.58
DANN	Benign	0.67
PhyloP100		-0.62
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: rs12437672; hg19: chr15-26838405;