5-162067984-GAAAA-GAAAAA

Variant names:

Variant summary

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

The NM_198904.4(GABRG2):c.-4dupA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,139,362 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 31)

Exomes 𝑓: 0.052 ( 0 hom. )

Consequence

GABRG2
NM_198904.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

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-G-GA is Benign according to our data. Variant chr5-162067984-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352636.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00193 (269/139314) while in subpopulation AFR AF = 0.00417 (159/38162). AF 95% confidence interval is 0.00364. There are 1 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 269 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.-4dupA	5_prime_UTR	Exon 1 of 10	NP_944494.1	P18507-2
GABRG2	NM_198903.2		c.-4dupA	5_prime_UTR	Exon 1 of 11	NP_944493.2	P18507-3
GABRG2	NM_001375343.1		c.-4dupA	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.-4dupA	5_prime_UTR	Exon 1 of 10	ENSP00000491909.2	P18507-2
GABRG2	ENST00000414552.6	TSL:1	c.-4dupA	5_prime_UTR	Exon 1 of 11	ENSP00000410732.2	P18507-3
GABRG2	ENST00000639111.2	TSL:1	c.-4dupA	5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

267

AN:

139270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00130

Gnomad ASJ

AF:

0.00364

Gnomad EAS

AF:

0.000624

Gnomad SAS

AF:

0.00390

Gnomad FIN

AF:

0.00109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000740

Gnomad OTH

AF:

0.00157

GnomAD2 exomes

AF:

0.0524

AC:

3637

AN:

69360

AF XY:

0.0541

show subpopulations

Gnomad AFR exome

AF:

0.0429

Gnomad AMR exome

AF:

0.0564

Gnomad ASJ exome

AF:

0.0597

Gnomad EAS exome

AF:

0.0499

Gnomad FIN exome

AF:

0.0452

Gnomad NFE exome

AF:

0.0449

Gnomad OTH exome

AF:

0.0499

GnomAD4 exome

AF:

0.0519

AC:

51900

AN:

1000048

Hom.:

Cov.:

AF XY:

0.0494

AC XY:

24800

AN XY:

502104

show subpopulations

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

African (AFR)

AF:

0.0495

AC:

1168

AN:

23578

American (AMR)

AF:

0.0258

AC:

853

AN:

33038

Ashkenazi Jewish (ASJ)

AF:

0.0370

AC:

686

AN:

18562

East Asian (EAS)

AF:

0.0291

AC:

796

AN:

27356

South Asian (SAS)

AF:

0.0283

AC:

1847

AN:

65374

European-Finnish (FIN)

AF:

0.0269

AC:

1006

AN:

37370

Middle Eastern (MID)

AF:

0.0310

AC:

133

AN:

4290

European-Non Finnish (NFE)

AF:

0.0580

AC:

43457

AN:

749098

Other (OTH)

AF:

0.0472

AC:

1954

AN:

41382

⚠️ 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: 0.262

Heterozygous variant carriers

6236

12472

18708

24944

31180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

2060

4120

6180

8240

10300

<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:

0.00193

AC:

269

AN:

139314

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

129

AN XY:

67450

show subpopulations

African (AFR)

AF:

0.00417

AC:

159

AN:

38162

American (AMR)

AF:

0.00129

AC:

AN:

13904

Ashkenazi Jewish (ASJ)

AF:

0.00364

AC:

AN:

3294

East Asian (EAS)

AF:

0.000626

AC:

AN:

4794

South Asian (SAS)

AF:

0.00392

AC:

AN:

4340

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

8268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000740

AC:

AN:

63488

Other (OTH)

AF:

0.00207

AC:

AN:

1930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0317

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)

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

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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