Genetic Variant NM_000807.4:c.255+138T>A (chr4-46332477-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000807.4(GABRA2):c.255+138T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 558,216 control chromosomes in the GnomAD database, including 3,700 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 0.088 ( 787 hom., cov: 32)

Exomes 𝑓: 0.11 ( 2913 hom. )

Consequence

GABRA2
NM_000807.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0540

Publications

3 publications found

Variant links:

Genes affected

GABRA2 (HGNC:4076): (gamma-aminobutyric acid type A receptor subunit alpha2) 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. At least 16 distinct subunits of GABA-A receptors have been identified. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

GABRA2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 78
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRA2 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=-0.89).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4 link	c.255+138T>A		intron_variant	Intron 4 of 9	ENST00000381620.9	NP_000798.2	P47869-1A0A024R9X6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA2	ENST00000381620.9 link	c.255+138T>A		intron_variant	Intron 4 of 9	1	NM_000807.4	ENSP00000371033.4		P47869-1

Frequencies

GnomAD3 genomes

AF:

0.0879

AC:

13367

AN:

152060

Hom.:

789

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0227

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.0434

Gnomad SAS

AF:

0.196

Gnomad FIN

AF:

0.0844

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.0958

GnomAD4 exome

AF:

0.111

AC:

45256

AN:

406038

Hom.:

2913

AF XY:

0.115

AC XY:

24918

AN XY:

216040

show subpopulations

African (AFR)

AF:

0.0195

AC:

207

AN:

10632

American (AMR)

AF:

0.111

AC:

1724

AN:

15496

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

1516

AN:

12268

East Asian (EAS)

AF:

0.0391

AC:

1113

AN:

28468

South Asian (SAS)

AF:

0.188

AC:

6456

AN:

34376

European-Finnish (FIN)

AF:

0.0860

AC:

3624

AN:

42134

Middle Eastern (MID)

AF:

0.127

AC:

231

AN:

1822

European-Non Finnish (NFE)

AF:

0.118

AC:

28012

AN:

237874

Other (OTH)

AF:

0.103

AC:

2373

AN:

22968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1837

3674

5510

7347

9184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.0878

AC:

13354

AN:

152178

Hom.:

787

Cov.:

AF XY:

0.0877

AC XY:

6524

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0226

AC:

939

AN:

41552

American (AMR)

AF:

0.109

AC:

1655

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

412

AN:

3472

East Asian (EAS)

AF:

0.0435

AC:

225

AN:

5172

South Asian (SAS)

AF:

0.196

AC:

943

AN:

4822

European-Finnish (FIN)

AF:

0.0844

AC:

895

AN:

10606

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8004

AN:

67988

Other (OTH)

AF:

0.0943

AC:

199

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

606

1213

1819

2426

3032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0467

Hom.:

Bravo

AF:

0.0849

Asia WGS

AF:

0.104

AC:

362

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.4

(source)

DANN

Benign

0.39

PhyloP100

0.054

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over