chr5-161854239-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001127644.2(GABRA1):c.156T>C(p.Gly52Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,596,510 control chromosomes in the GnomAD database, including 55,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4775 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51195 hom. )

Consequence

GABRA1
NM_001127644.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.550

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-161854239-T-C is Benign according to our data. Variant chr5-161854239-T-C is described in ClinVar as Benign. ClinVar VariationId is 129123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA1	NM_001127644.2 link	c.156T>C	p.Gly52Gly	synonymous_variant	Exon 3 of 10	ENST00000393943.10	NP_001121116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA1	ENST00000393943.10 link	c.156T>C	p.Gly52Gly	synonymous_variant	Exon 3 of 10	1	NM_001127644.2	ENSP00000377517.4

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36136

AN:

151328

Hom.:

4770

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.302

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.359

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.264

AC:

66172

AN:

250770

AF XY:

0.268

show subpopulations

Gnomad AFR exome

AF:

0.127

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.274

GnomAD4 exome

AF:

0.263

AC:

380104

AN:

1445064

Hom.:

51195

Cov.:

AF XY:

0.264

AC XY:

190202

AN XY:

719828

show subpopulations

African (AFR)

AF:

0.125

AC:

4145

AN:

33140

American (AMR)

AF:

0.220

AC:

9844

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6654

AN:

25980

East Asian (EAS)

AF:

0.287

AC:

11365

AN:

39558

South Asian (SAS)

AF:

0.257

AC:

22073

AN:

85904

European-Finnish (FIN)

AF:

0.350

AC:

18668

AN:

53376

Middle Eastern (MID)

AF:

0.273

AC:

1569

AN:

5738

European-Non Finnish (NFE)

AF:

0.264

AC:

290032

AN:

1096884

Other (OTH)

AF:

0.263

AC:

15754

AN:

59824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

12130

24259

36389

48518

60648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9498

18996

28494

37992

47490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.239

AC:

36146

AN:

151446

Hom.:

4775

Cov.:

AF XY:

0.242

AC XY:

17906

AN XY:

74010

show subpopulations

African (AFR)

AF:

0.129

AC:

5359

AN:

41452

American (AMR)

AF:

0.239

AC:

3624

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

926

AN:

3458

East Asian (EAS)

AF:

0.303

AC:

1555

AN:

5140

South Asian (SAS)

AF:

0.266

AC:

1276

AN:

4800

European-Finnish (FIN)

AF:

0.359

AC:

3781

AN:

10530

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18629

AN:

67584

Other (OTH)

AF:

0.262

AC:

551

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1378

2755

4133

5510

6888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.257

Hom.:

3156

Bravo

AF:

0.224

Asia WGS

AF:

0.275

AC:

954

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.286

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 40. Only high quality variants are reported. -

not provided

Benign:2

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Idiopathic generalized epilepsy;C1970160:Epilepsy, childhood absence 4;C4013473:Epilepsy, idiopathic generalized, susceptibility to, 13

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epilepsy, idiopathic generalized, susceptibility to, 13

Benign:1

Jan 13, 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. -

Developmental and epileptic encephalopathy, 19

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.2

(source)

DANN

Benign

0.71

PhyloP100

-0.55

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over