Genetic Variant NM_000807.4:c.-11+179A>T (chr4-46389556-T-A) – 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.-11+179A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 408,946 control chromosomes in the GnomAD database, including 17,565 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 0.27 ( 6710 hom., cov: 29)

Exomes 𝑓: 0.28 ( 10855 hom. )

Consequence

GABRA2
NM_000807.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.494

Publications

11 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=-0.77).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4 link	c.-11+179A>T		intron_variant	Intron 1 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.-11+179A>T		intron_variant	Intron 1 of 9	1	NM_000807.4	ENSP00000371033.4		P47869-1

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41038

AN:

151448

Hom.:

6695

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.0980

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.657

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.275

GnomAD4 exome

AF:

0.278

AC:

71543

AN:

257380

Hom.:

10855

Cov.:

AF XY:

0.277

AC XY:

33779

AN XY:

122120

show subpopulations

African (AFR)

AF:

0.0892

AC:

445

AN:

4986

American (AMR)

AF:

0.460

AC:

126

AN:

274

Ashkenazi Jewish (ASJ)

AF:

0.226

AC:

352

AN:

1560

East Asian (EAS)

AF:

0.636

AC:

611

AN:

960

South Asian (SAS)

AF:

0.400

AC:

2023

AN:

5052

European-Finnish (FIN)

AF:

0.275

AC:

AN:

Middle Eastern (MID)

AF:

0.214

AC:

113

AN:

528

European-Non Finnish (NFE)

AF:

0.277

AC:

65394

AN:

235660

Other (OTH)

AF:

0.297

AC:

2457

AN:

8280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2418

4836

7255

9673

12091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2938

5876

8814

11752

14690

<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:

0.271

AC:

41065

AN:

151566

Hom.:

6710

Cov.:

AF XY:

0.281

AC XY:

20809

AN XY:

73978

show subpopulations

African (AFR)

AF:

0.124

AC:

5141

AN:

41328

American (AMR)

AF:

0.424

AC:

6456

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

818

AN:

3464

East Asian (EAS)

AF:

0.658

AC:

3324

AN:

5054

South Asian (SAS)

AF:

0.454

AC:

2182

AN:

4802

European-Finnish (FIN)

AF:

0.310

AC:

3247

AN:

10472

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19167

AN:

67910

Other (OTH)

AF:

0.279

AC:

588

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1379

2757

4136

5514

6893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.263

Hom.:

767

Bravo

AF:

0.274

Asia WGS

AF:

0.546

AC:

1898

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.49

PromoterAI

-0.018

Neutral

(source)

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