rs998754

Positions:

• chr5-161898928-A-C
• chr5-161898928-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001127644.2(GABRA1):​c.*1506A>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 0.598 in 152,354 control chromosomes in the GnomAD database, including 27,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.60 (27596 hom., cov: 32)
  • Exomes 𝑓: 0.50 (52 hom.)
• Consequence: GABRA1 NM_001127644.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51

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]

GABRA1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-161898928-A-C is Benign according to our data. Variant chr5-161898928-A-C is described in ClinVar as [Benign]. Clinvar id is 352614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.*1506A>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.*1506A>C		3_prime_UTR_variant	10/10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90860 AN: 151804 Hom.: 27561 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.505 AC: 218 AN: 432 Hom.: 52 Cov.: 0 AF XY: 0.496 AC XY: 129 AN XY: 260

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.599 AC: 90949 AN: 151922 Hom.: 27596 Cov.: 32 AF XY: 0.596 AC XY: 44265 AN XY: 74246

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.684

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.593

Alfa AF: 0.619 Hom.: 36732

Bravo AF: 0.605

Asia WGS AF: 0.524 AC: 1816 AN: 3462

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	-0.44
CADD	Benign	11
DANN	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs998754; hg19: chr5-161325934; COSMIC: COSV50100437; COSMIC: COSV50100437;