rs17545383

Variant names:

• chr5-161895250-C-G
• rs17545383
• NM_001127644.2:c.857-416C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127644.2(GABRA1):​c.857-416C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 151,826 control chromosomes in the GnomAD database, including 18,732 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18732 hom., cov: 31)
• Consequence: GABRA1 NM_001127644.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 2 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2	c.857-416C>G		intron_variant	Intron 8 of 9	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10	c.857-416C>G		intron_variant	Intron 8 of 9	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73740 AN: 151708 Hom.: 18708 Cov.: 31

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.485

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.486 AC: 73788 AN: 151826 Hom.: 18732 Cov.: 31 AF XY: 0.483 AC XY: 35816 AN XY: 74148

African (AFR) AF: 0.370 AC: 15337 AN: 41412

American (AMR) AF: 0.574 AC: 8756 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1754 AN: 3466

East Asian (EAS) AF: 0.348 AC: 1786 AN: 5126

South Asian (SAS) AF: 0.386 AC: 1862 AN: 4824

European-Finnish (FIN) AF: 0.483 AC: 5064 AN: 10490

Middle Eastern (MID) AF: 0.448 AC: 130 AN: 290

European-Non Finnish (NFE) AF: 0.554 AC: 37624 AN: 67938

Other (OTH) AF: 0.480 AC: 1013 AN: 2112

Alfa AF: 0.517 Hom.: 2600

Bravo AF: 0.485

Asia WGS AF: 0.342 AC: 1192 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.73
DANN	Benign	0.56
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17545383; hg19: chr5-161322256; COSMIC: COSV50100420; COSMIC: COSV50100420;