dbSNP rs4340950: GABRA1:c.75-521A>G (chr5-161853637-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001127644.2(GABRA1):c.75-521A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 151,882 control chromosomes in the GnomAD database, including 1,963 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 0.15 ( 1963 hom., cov: 32)

Exomes 𝑓: 0.056 ( 0 hom. )

Consequence

GABRA1
NM_001127644.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.798

Publications

0 publications found

Variant links:

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

GABRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2 link	c.75-521A>G		intron_variant	Intron 2 of 9	ENST00000393943.10	NP_001121116.1	P14867

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10 link	c.75-521A>G		intron_variant	Intron 2 of 9	1	NM_001127644.2	ENSP00000377517.4		P14867

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22311

AN:

151692

Hom.:

1962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0823

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.279

Gnomad SAS

AF:

0.223

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.130

GnomAD4 exome

AF:

0.0556

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0652

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0333

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.147

AC:

22315

AN:

151810

Hom.:

1963

Cov.:

AF XY:

0.149

AC XY:

11043

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.222

AC:

9185

AN:

41464

American (AMR)

AF:

0.0822

AC:

1251

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

369

AN:

3466

East Asian (EAS)

AF:

0.279

AC:

1441

AN:

5162

South Asian (SAS)

AF:

0.223

AC:

1075

AN:

4822

European-Finnish (FIN)

AF:

0.115

AC:

1222

AN:

10602

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7429

AN:

67752

Other (OTH)

AF:

0.128

AC:

270

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

926

1852

2779

3705

4631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.111

Hom.:

1168

Bravo

AF:

0.148

Asia WGS

AF:

0.227

AC:

785

AN:

3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over