dbSNP rs3756007: GABRA2:c.-10-331A>G (chr4-46389047-T-C) – 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.-10-331A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 1,076,532 control chromosomes in the GnomAD database, including 2,153 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 0.057 ( 516 hom., cov: 30)

Exomes 𝑓: 0.053 ( 1637 hom. )

Consequence

GABRA2
NM_000807.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.94

Publications

7 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=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA2	NM_000807.4 link	c.-10-331A>G		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.-10-331A>G		intron_variant	Intron 1 of 9	1	NM_000807.4	ENSP00000371033.4		P47869-1

Frequencies

GnomAD3 genomes

AF:

0.0571

AC:

8658

AN:

151608

Hom.:

512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.159

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.0401

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0567

GnomAD4 exome

AF:

0.0533

AC:

49248

AN:

924808

Hom.:

1637

Cov.:

AF XY:

0.0527

AC XY:

22822

AN XY:

433112

show subpopulations

African (AFR)

AF:

0.00639

AC:

118

AN:

18476

American (AMR)

AF:

0.220

AC:

1019

AN:

4640

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

133

AN:

8230

East Asian (EAS)

AF:

0.195

AC:

1852

AN:

9504

South Asian (SAS)

AF:

0.0348

AC:

910

AN:

26182

European-Finnish (FIN)

AF:

0.0972

AC:

415

AN:

4268

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

2042

European-Non Finnish (NFE)

AF:

0.0521

AC:

42653

AN:

818658

Other (OTH)

AF:

0.0646

AC:

2118

AN:

32808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2525

5050

7576

10101

12626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2084

4168

6252

8336

10420

<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:

0.0571

AC:

8669

AN:

151724

Hom.:

516

Cov.:

AF XY:

0.0624

AC XY:

4628

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.0119

AC:

493

AN:

41320

American (AMR)

AF:

0.160

AC:

2433

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.208

AC:

1070

AN:

5142

South Asian (SAS)

AF:

0.0398

AC:

191

AN:

4802

European-Finnish (FIN)

AF:

0.108

AC:

1131

AN:

10474

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0465

AC:

3158

AN:

67962

Other (OTH)

AF:

0.0561

AC:

118

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

395

790

1186

1581

1976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0443

Hom.:

226

Bravo

AF:

0.0646

Asia WGS

AF:

0.145

AC:

501

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

1.7

(source)

DANN

Benign

0.59

PhyloP100

-1.9

PromoterAI

0.12

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