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_000806.5(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_000806.5 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000806.5. 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
	GABRA1	NM_001127644.2	MANE Select	c.*470A>G		3_prime_UTR	Exon 10 of 10	NP_001121116.1
	GABRA1	NM_000806.5		c.*470A>G		3_prime_UTR	Exon 11 of 11	NP_000797.2
	GABRA1	NM_001127643.2		c.*470A>G		3_prime_UTR	Exon 11 of 11	NP_001121115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRA1	ENST00000393943.10	TSL:1 MANE Select	c.*470A>G		3_prime_UTR	Exon 10 of 10	ENSP00000377517.4
	GABRA1	ENST00000428797.7	TSL:1	c.*470A>G		3_prime_UTR	Exon 11 of 11	ENSP00000393097.2
	GABRA1	ENST00000437025.6	TSL:1	c.*470A>G		3_prime_UTR	Exon 10 of 10	ENSP00000415441.2

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, idiopathic generalized, susceptibility to, 13 (1)

Computational scores

Source: dbNSFP v4.9

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;