NM_000814.6:c.240+26898C>T

Variant names:

• chr15-26745504-G-A
• rs8038471
• NM_000814.6:c.240+26898C>T

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+26898C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 151,820 control chromosomes in the GnomAD database, including 16,373 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 0.45 (16373 hom., cov: 31)
• Consequence: GABRB3 NM_000814.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184
• Publications: 7 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

LOC112268151 (HGNC:):

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 (AMR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRB3	NM_000814.6	c.240+26898C>T		intron_variant	Intron 3 of 8	ENST00000311550.10	NP_000805.1
LOC112268151	XR_002957720.2	n.9446C>T		non_coding_transcript_exon_variant	Exon 2 of 2
GABRB3	NM_021912.5	c.240+26898C>T		intron_variant	Intron 3 of 8		NP_068712.1
GABRB3	NM_001278631.2	c.-112+26898C>T		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+26898C>T		intron_variant	Intron 3 of 8	1	NM_000814.6	ENSP00000308725.5

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67860 AN: 151700 Hom.: 16359 Cov.: 31

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.465

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

GnomAD4 genome AF: 0.447 AC: 67901 AN: 151820 Hom.: 16373 Cov.: 31 AF XY: 0.451 AC XY: 33445 AN XY: 74160

African (AFR) AF: 0.258 AC: 10676 AN: 41430

American (AMR) AF: 0.593 AC: 9039 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1577 AN: 3470

East Asian (EAS) AF: 0.567 AC: 2903 AN: 5116

South Asian (SAS) AF: 0.574 AC: 2757 AN: 4800

European-Finnish (FIN) AF: 0.479 AC: 5033 AN: 10514

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34415 AN: 67934

Other (OTH) AF: 0.470 AC: 988 AN: 2104

Alfa AF: 0.489 Hom.: 72853

Bravo AF: 0.447

Asia WGS AF: 0.599 AC: 2084 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	2.1
DANN	Benign	0.81
PhyloP100		0.18
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: rs8038471; hg19: chr15-26990651;