rs2290732

Variant names:

• chr5-161897892-A-G
• rs2290732
• NM_001127644.2:c.*470A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-161897892-A-G
• chr5-161897892-A-T

Variant summary

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

The NM_001127644.2(GABRA1):​c.*470A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.598 in 154,248 control chromosomes in the GnomAD database, including 28,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.60 (27556 hom., cov: 31)
  • Exomes 𝑓: 0.60 (471 hom.)
• Consequence: GABRA1 NM_001127644.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.31
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 19

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 13

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile myoclonic epilepsy

  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=-0.44).
• BP6: Variant 5-161897892-A-G is Benign according to our data. Variant chr5-161897892-A-G is described in ClinVar as Benign. ClinVar VariationId is 352608.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 rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.*470A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.*470A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90725 AN: 151682 Hom.: 27520 Cov.: 31

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.599 AC: 1464 AN: 2446 Hom.: 471 Cov.: 0 AF XY: 0.605 AC XY: 811 AN XY: 1340

African (AFR) AF: 0.417 AC: 5 AN: 12

American (AMR) AF: 0.678 AC: 175 AN: 258

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 11 AN: 26

East Asian (EAS) AF: 0.333 AC: 16 AN: 48

South Asian (SAS) AF: 0.500 AC: 105 AN: 210

European-Finnish (FIN) AF: 0.500 AC: 20 AN: 40

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.613 AC: 1088 AN: 1776

Other (OTH) AF: 0.597 AC: 43 AN: 72

GnomAD4 genome AF: 0.598 AC: 90816 AN: 151802 Hom.: 27556 Cov.: 31 AF XY: 0.596 AC XY: 44189 AN XY: 74174

African (AFR) AF: 0.562 AC: 23282 AN: 41400

American (AMR) AF: 0.684 AC: 10418 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2045 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2374 AN: 5144

South Asian (SAS) AF: 0.553 AC: 2656 AN: 4806

European-Finnish (FIN) AF: 0.538 AC: 5659 AN: 10516

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42488 AN: 67906

Other (OTH) AF: 0.593 AC: 1252 AN: 2112

Alfa AF: 0.616 Hom.: 53534

Bravo AF: 0.605

Asia WGS AF: 0.526 AC: 1827 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	14
DANN	Benign	0.88
PhyloP100		5.3
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: rs2290732; hg19: chr5-161324898; COSMIC: COSV50100435; COSMIC: COSV50100435;