rs12658835

Positions:

• chr5-161848296-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000393943.10(GABRA1):​c.-142A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 151,944 control chromosomes in the GnomAD database, including 3,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3304 hom., cov: 30)
  • Exomes 𝑓: 0.17 (3 hom.)
• Consequence: GABRA1 ENST00000393943.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.05

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]

LOC105377696 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-161848296-A-G is Benign according to our data. Variant chr5-161848296-A-G is described in ClinVar as [Benign]. Clinvar id is 352592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.-142A>G		5_prime_UTR_variant	1/10	ENST00000393943.10	NP_001121116.1
LOC105377696	XR_941158.4	n.74+2224T>C		intron_variant, non_coding_transcript_variant
GABRA1	NM_000806.5	c.-142A>G		5_prime_UTR_variant	2/11		NP_000797.2
GABRA1	NM_001127643.2	c.-142A>G		5_prime_UTR_variant	2/11		NP_001121115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.-142A>G		5_prime_UTR_variant	1/10	1	NM_001127644.2	ENSP00000377517	P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28318 AN: 151656 Hom.: 3301 Cov.: 30

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.169 AC: 29 AN: 172 Hom.: 3 Cov.: 0 AF XY: 0.184 AC XY: 21 AN XY: 114

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.187 AC: 28328 AN: 151772 Hom.: 3304 Cov.: 30 AF XY: 0.190 AC XY: 14096 AN XY: 74150

Gnomad4 AFR AF: 0.0534

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.274

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.212

Alfa AF: 0.183 Hom.: 455

Bravo AF: 0.173

Asia WGS AF: 0.231 AC: 802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs12658835; hg19: chr5-161275302;