rs4906902

Variant names:

• chr15-26774621-A-G
• rs4906902
• ENST00000541819.6:c.249-1849T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The ENST00000541819.6(GABRB3):​c.249-1849T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,194 control chromosomes in the GnomAD database, including 2,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.16 (2626 hom., cov: 33)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.298
• Publications: 31 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=-0.27).
• BP6: Variant 15-26774621-A-G is Benign according to our data. Variant chr15-26774621-A-G is described in ClinVar as Benign. ClinVar VariationId is 3762491.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541819.6. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000541819.6	TSL:1	c.249-1849T>C		intron	N/A	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000557641.5	TSL:5	n.453-1849T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24108 AN: 152076 Hom.: 2616 Cov.: 33

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.167

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

GnomAD4 genome AF: 0.158 AC: 24122 AN: 152194 Hom.: 2626 Cov.: 33 AF XY: 0.166 AC XY: 12358 AN XY: 74392

African (AFR) AF: 0.0393 AC: 1634 AN: 41540

American (AMR) AF: 0.321 AC: 4904 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1629 AN: 5168

South Asian (SAS) AF: 0.240 AC: 1157 AN: 4818

European-Finnish (FIN) AF: 0.203 AC: 2146 AN: 10592

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11646 AN: 67998

Other (OTH) AF: 0.166 AC: 352 AN: 2116

Alfa AF: 0.116 Hom.: 401

Bravo AF: 0.162

Asia WGS AF: 0.267 AC: 927 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.66
PhyloP100		0.30
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4906902; hg19: chr15-27019768;