rs2290733

Positions:

• chr5-161899351-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127644.2(GABRA1):​c.*1929T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 152,676 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (120 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (0 hom.)
• Consequence: GABRA1 NM_001127644.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08

Genes affected

GABRA1 (HGNC:4075): (gamma-aminobutyric acid type A receptor subunit alpha1) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-161899351-T-C is Benign according to our data. Variant chr5-161899351-T-C is described in ClinVar as [Benign]. Clinvar id is 352622.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.*1929T>C		3_prime_UTR_variant	10/10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.*1929T>C		3_prime_UTR_variant	10/10	1	NM_001127644.2	ENSP00000377517	P1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2334 AN: 152134 Hom.: 119 Cov.: 33

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00708 AC: 3 AN: 424 Hom.: 0 Cov.: 0 AF XY: 0.00775 AC XY: 2 AN XY: 258

Gnomad4 FIN exome AF: 0.00721

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0153 AC: 2330 AN: 152252 Hom.: 120 Cov.: 33 AF XY: 0.0158 AC XY: 1174 AN XY: 74450

Gnomad4 AFR AF: 0.00423

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0119 Hom.: 9

Bravo AF: 0.0167

Asia WGS AF: 0.0920 AC: 320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, idiopathic generalized, susceptibility to, 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.6
DANN	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2290733; hg19: chr5-161326357;