ENST00000541819.6:c.249-1018C>G

Variant names:

• chr15-26773790-G-C
• rs20317
• ENST00000541819.6:c.249-1018C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000541819.6(GABRB3):​c.249-1018C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,443,350 control chromosomes in the GnomAD database, including 25,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2446 hom., cov: 29)
  • Exomes 𝑓: 0.18 (22843 hom.)
• Consequence: GABRB3 ENST00000541819.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.43
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-26773790-G-C is Benign according to our data. Variant chr15-26773790-G-C is described in ClinVar as Benign. ClinVar VariationId is 681728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.299 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
	GABRB3	NM_021912.5		c.-66C>G		upstream_gene	N/A	NP_068712.1	X5DQY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRB3	ENST00000541819.6	TSL:1	c.249-1018C>G		intron	N/A	ENSP00000442408.2	F5H7N0
	GABRB3	ENST00000638099.1	TSL:5	c.-20+153C>G		intron	N/A	ENSP00000490678.1	A0A1B0GVW3
	GABRB3	ENST00000557641.5	TSL:5	n.453-1018C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.152 AC: 22772 AN: 150116 Hom.: 2436 Cov.: 29

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.178 AC: 230764 AN: 1293124 Hom.: 22843 Cov.: 19 AF XY: 0.180 AC XY: 115507 AN XY: 641708

African (AFR) AF: 0.0301 AC: 883 AN: 29370

American (AMR) AF: 0.384 AC: 13437 AN: 34968

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3088 AN: 24302

East Asian (EAS) AF: 0.337 AC: 11655 AN: 34552

South Asian (SAS) AF: 0.221 AC: 16978 AN: 76734

European-Finnish (FIN) AF: 0.198 AC: 9396 AN: 47444

Middle Eastern (MID) AF: 0.137 AC: 567 AN: 4146

European-Non Finnish (NFE) AF: 0.168 AC: 165448 AN: 987456

Other (OTH) AF: 0.172 AC: 9312 AN: 54152

GnomAD4 genome AF: 0.152 AC: 22787 AN: 150226 Hom.: 2446 Cov.: 29 AF XY: 0.158 AC XY: 11564 AN XY: 73172

African (AFR) AF: 0.0373 AC: 1542 AN: 41338

American (AMR) AF: 0.307 AC: 4598 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3460

East Asian (EAS) AF: 0.303 AC: 1479 AN: 4874

South Asian (SAS) AF: 0.228 AC: 1061 AN: 4660

European-Finnish (FIN) AF: 0.191 AC: 1949 AN: 10230

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.166 AC: 11189 AN: 67416

Other (OTH) AF: 0.158 AC: 328 AN: 2070

Alfa AF: 0.0547 Hom.: 77

Bravo AF: 0.160

Asia WGS AF: 0.247 AC: 836 AN: 3384

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.65
DANN	Benign	0.73
PhyloP100		-1.4
PromoterAI		-0.046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs20317; hg19: chr15-27018937;