rs2912582

Variant names:

• chr15-26547243-A-G
• rs2912582
• NM_000814.6:c.*550T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000814.6(GABRB3):​c.*550T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 315,870 control chromosomes in the GnomAD database, including 415 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 0.038 (367 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (48 hom.)
• Consequence: GABRB3 NM_000814.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.514
• Publications: 1 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	NM_000814.6	MANE Select	c.*550T>C		3_prime_UTR	Exon 9 of 9	NP_000805.1
	GABRB3	NM_021912.5		c.*550T>C		3_prime_UTR	Exon 9 of 9	NP_068712.1
	GABRB3	NM_001191321.3		c.*550T>C		3_prime_UTR	Exon 7 of 7	NP_001178250.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.*550T>C		3_prime_UTR	Exon 9 of 9	ENSP00000308725.5
	GABRB3	ENST00000541819.6	TSL:1	c.*550T>C		3_prime_UTR	Exon 10 of 10	ENSP00000442408.2
	GABRB3	ENST00000299267.9	TSL:1	c.*550T>C		3_prime_UTR	Exon 9 of 9	ENSP00000299267.4

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5769 AN: 152186 Hom.: 362 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.00727 AC: 1189 AN: 163566 Hom.: 48 Cov.: 0 AF XY: 0.00659 AC XY: 543 AN XY: 82452

African (AFR) AF: 0.127 AC: 700 AN: 5500

American (AMR) AF: 0.0126 AC: 71 AN: 5630

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 85 AN: 6644

East Asian (EAS) AF: 0.00 AC: 0 AN: 15342

South Asian (SAS) AF: 0.000584 AC: 1 AN: 1712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10266

Middle Eastern (MID) AF: 0.0208 AC: 18 AN: 864

European-Non Finnish (NFE) AF: 0.00137 AC: 146 AN: 106386

Other (OTH) AF: 0.0150 AC: 168 AN: 11222

GnomAD4 genome AF: 0.0381 AC: 5803 AN: 152304 Hom.: 367 Cov.: 32 AF XY: 0.0361 AC XY: 2690 AN XY: 74482

African (AFR) AF: 0.128 AC: 5329 AN: 41552

American (AMR) AF: 0.0164 AC: 251 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68024

Other (OTH) AF: 0.0379 AC: 80 AN: 2112

Alfa AF: 0.0236 Hom.: 89

Bravo AF: 0.0433

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.27
DANN	Benign	0.55
PhyloP100		0.51
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: rs2912582; hg19: chr15-26792390;