5-162067984-GAAAA-GAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_198904.4(GABRG2):c.-4delA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 908,344 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0088 ( 12 hom., cov: 31)

Exomes 𝑓: 0.13 ( 7 hom. )

Consequence

GABRG2
NM_198904.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.142

Publications

1 publications found

Variant links:

Genes affected

GABRG2 (HGNC:4087): (gamma-aminobutyric acid type A receptor subunit gamma2) This gene encodes a gamma-aminobutyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the mammlian brain, where it acts at GABA-A receptors, which are ligand-gated chloride channels. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene have been associated with epilepsy and febrile seizures. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

GABRG2 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 74
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 8
Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Dravet syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized epilepsy with febrile seizures plus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
self-limited epilepsy with centrotemporal spikes
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GABRG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 5-162067984-GA-G is Benign according to our data. Variant chr5-162067984-GA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352637.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00882 (1227/139132) while in subpopulation AFR AF = 0.028 (1069/38130). AF 95% confidence interval is 0.0266. There are 12 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1227 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198904.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GABRG2	NM_198904.4	MANE Select	c.-4delA	5_prime_UTR	Exon 1 of 10	NP_944494.1	P18507-2
GABRG2	NM_198903.2		c.-4delA	5_prime_UTR	Exon 1 of 11	NP_944493.2	P18507-3
GABRG2	NM_001375343.1		c.-4delA	5_prime_UTR	Exon 1 of 10	NP_001362272.1	A0A1X7SBZ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.-4delA	5_prime_UTR	Exon 1 of 10	ENSP00000491909.2	P18507-2
GABRG2	ENST00000414552.6	TSL:1	c.-4delA	5_prime_UTR	Exon 1 of 11	ENSP00000410732.2	P18507-3
GABRG2	ENST00000639111.2	TSL:1	c.-4delA	5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1224

AN:

139092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.000609

Gnomad EAS

AF:

0.000208

Gnomad SAS

AF:

0.000919

Gnomad FIN

AF:

0.00378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000757

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.323

AC:

22436

AN:

69360

AF XY:

0.327

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.340

Gnomad ASJ exome

AF:

0.340

Gnomad EAS exome

AF:

0.337

Gnomad FIN exome

AF:

0.297

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.135

AC:

103691

AN:

769212

Hom.:

Cov.:

AF XY:

0.136

AC XY:

50698

AN XY:

373124

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.177

AC:

3175

AN:

17970

American (AMR)

AF:

0.192

AC:

3693

AN:

19246

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

2014

AN:

11528

East Asian (EAS)

AF:

0.184

AC:

3103

AN:

16856

South Asian (SAS)

AF:

0.135

AC:

4627

AN:

34192

European-Finnish (FIN)

AF:

0.170

AC:

4394

AN:

25776

Middle Eastern (MID)

AF:

0.0991

AC:

336

AN:

3392

European-Non Finnish (NFE)

AF:

0.128

AC:

77824

AN:

609888

Other (OTH)

AF:

0.149

AC:

4525

AN:

30364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

13500

27000

40500

54000

67500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2970

5940

8910

11880

14850

<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:

0.00882

AC:

1227

AN:

139132

Hom.:

Cov.:

AF XY:

0.00852

AC XY:

574

AN XY:

67384

show subpopulations

African (AFR)

AF:

0.0280

AC:

1069

AN:

38130

American (AMR)

AF:

0.00432

AC:

AN:

13892

Ashkenazi Jewish (ASJ)

AF:

0.000609

AC:

AN:

3282

East Asian (EAS)

AF:

0.000209

AC:

AN:

4792

South Asian (SAS)

AF:

0.00115

AC:

AN:

4340

European-Finnish (FIN)

AF:

0.00378

AC:

AN:

8208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.000757

AC:

AN:

63424

Other (OTH)

AF:

0.00569

AC:

AN:

1932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.114

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Generalized epilepsy with febrile seizures plus (1)

Inborn genetic diseases (1)

not provided (1)

Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.14

Mutation Taster

=300/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over