NM_000814.6:c.1081-4918A>G

Variant names:

• chr15-26553052-T-C
• rs2081648
• NM_000814.6:c.1081-4918A>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.1081-4918A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,268 control chromosomes in the GnomAD database, including 2,418 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 0.13 (2418 hom., cov: 33)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.193
• Publications: 16 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.1081-4918A>G		intron_variant	Intron 8 of 8	ENST00000311550.10	NP_000805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10	c.1081-4918A>G		intron_variant	Intron 8 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19481 AN: 152150 Hom.: 2412 Cov.: 33

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.128

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

GnomAD4 genome AF: 0.128 AC: 19501 AN: 152268 Hom.: 2418 Cov.: 33 AF XY: 0.135 AC XY: 10068 AN XY: 74452

African (AFR) AF: 0.0400 AC: 1665 AN: 41576

American (AMR) AF: 0.176 AC: 2699 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3472

East Asian (EAS) AF: 0.704 AC: 3647 AN: 5178

South Asian (SAS) AF: 0.246 AC: 1186 AN: 4822

European-Finnish (FIN) AF: 0.138 AC: 1459 AN: 10606

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8029 AN: 68002

Other (OTH) AF: 0.129 AC: 273 AN: 2114

Alfa AF: 0.107 Hom.: 652

Bravo AF: 0.130

Asia WGS AF: 0.405 AC: 1406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.3
DANN	Benign	0.44
PhyloP100		0.19
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: rs2081648; hg19: chr15-26798199;