rs1367959

Variant names:

• chr15-26672011-C-T
• rs1367959
• NM_000814.6:c.241-50477G>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.241-50477G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 151,948 control chromosomes in the GnomAD database, including 5,291 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 0.24 (5291 hom., cov: 32)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.138
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.321 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.241-50477G>A		intron	N/A	NP_000805.1	P28472-1
	GABRB3	NM_021912.5		c.241-50477G>A		intron	N/A	NP_068712.1	X5DQY4
	GABRB3	NM_001191320.2		c.-16+44603G>A		intron	N/A	NP_001178249.1	P28472-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000311550.10	TSL:1 MANE Select	c.241-50477G>A		intron	N/A	ENSP00000308725.5	P28472-1
	GABRB3	ENST00000541819.6	TSL:1	c.409-50477G>A		intron	N/A	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000299267.9	TSL:1	c.241-50477G>A		intron	N/A	ENSP00000299267.4	P28472-2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36160 AN: 151830 Hom.: 5286 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.238 AC: 36171 AN: 151948 Hom.: 5291 Cov.: 32 AF XY: 0.241 AC XY: 17904 AN XY: 74256

African (AFR) AF: 0.0612 AC: 2539 AN: 41456

American (AMR) AF: 0.329 AC: 5023 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 689 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1649 AN: 5152

South Asian (SAS) AF: 0.323 AC: 1554 AN: 4810

European-Finnish (FIN) AF: 0.327 AC: 3445 AN: 10528

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20407 AN: 67948

Other (OTH) AF: 0.239 AC: 505 AN: 2110

Alfa AF: 0.280 Hom.: 4696

Bravo AF: 0.231

Asia WGS AF: 0.324 AC: 1128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.38
PhyloP100		-0.14
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: rs1367959; hg19: chr15-26917158;