rs2162241

Variant names:

• chr15-26731635-T-C
• rs2162241
• NM_000814.6:c.240+40767A>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.240+40767A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 152,000 control chromosomes in the GnomAD database, including 30,422 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 0.63 (30422 hom., cov: 32)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.240+40767A>G		intron_variant	Intron 3 of 8	ENST00000311550.10	NP_000805.1
GABRB3	NM_021912.5	c.240+40767A>G		intron_variant	Intron 3 of 8		NP_068712.1
GABRB3	NM_001278631.2	c.-112+40767A>G		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.240+40767A>G		intron_variant	Intron 3 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.629 AC: 95458 AN: 151882 Hom.: 30398 Cov.: 32

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.630

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

GnomAD4 genome AF: 0.628 AC: 95529 AN: 152000 Hom.: 30422 Cov.: 32 AF XY: 0.630 AC XY: 46786 AN XY: 74266

African (AFR) AF: 0.579 AC: 23971 AN: 41432

American (AMR) AF: 0.727 AC: 11103 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2319 AN: 3470

East Asian (EAS) AF: 0.894 AC: 4607 AN: 5154

South Asian (SAS) AF: 0.712 AC: 3435 AN: 4822

European-Finnish (FIN) AF: 0.574 AC: 6056 AN: 10556

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42064 AN: 67976

Other (OTH) AF: 0.632 AC: 1331 AN: 2106

Alfa AF: 0.621 Hom.: 10972

Bravo AF: 0.639

Asia WGS AF: 0.825 AC: 2871 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.45
DANN	Benign	0.53
PhyloP100		-2.2
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: rs2162241; hg19: chr15-26976782;