Genetic Variant GABRG2:c.-5_-4delAA (chr5-162067984-GAA-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198904.4(GABRG2):c.-5_-4delAA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,253,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

GABRG2
NM_198904.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.819

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.-5_-4delAA	5_prime_UTR	Exon 1 of 10	NP_944494.1	P18507-2
GABRG2	NM_198903.2		c.-5_-4delAA	5_prime_UTR	Exon 1 of 11	NP_944493.2	P18507-3
GABRG2	NM_001375343.1		c.-5_-4delAA	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.-5_-4delAA	5_prime_UTR	Exon 1 of 10	ENSP00000491909.2	P18507-2
GABRG2	ENST00000414552.6	TSL:1	c.-5_-4delAA	5_prime_UTR	Exon 1 of 11	ENSP00000410732.2	P18507-3
GABRG2	ENST00000639111.2	TSL:1	c.-5_-4delAA	5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes

AF:

0.0000143

AC:

AN:

139378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000719

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00161

AC:

112

AN:

69360

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.000910

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.00339

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000428

AC:

477

AN:

1114258

Hom.:

AF XY:

0.000399

AC XY:

224

AN XY:

561226

show subpopulations

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

African (AFR)

AF:

0.000421

AC:

AN:

26126

American (AMR)

AF:

0.000131

AC:

AN:

38124

Ashkenazi Jewish (ASJ)

AF:

0.000281

AC:

AN:

21324

East Asian (EAS)

AF:

0.000189

AC:

AN:

31716

South Asian (SAS)

AF:

0.000253

AC:

AN:

75000

European-Finnish (FIN)

AF:

0.000982

AC:

AN:

41734

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4684

European-Non Finnish (NFE)

AF:

0.000448

AC:

371

AN:

828916

Other (OTH)

AF:

0.000386

AC:

AN:

46634

⚠️ 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: 0.241

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000143

AC:

AN:

139422

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

67526

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

38166

American (AMR)

AF:

0.0000719

AC:

AN:

13916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3296

East Asian (EAS)

AF:

0.00

AC:

AN:

4792

South Asian (SAS)

AF:

0.00

AC:

AN:

4342

European-Finnish (FIN)

AF:

0.000121

AC:

AN:

8282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63562

Other (OTH)

AF:

0.00

AC:

AN:

1932

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.250

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:

0.00124

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.82

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.

5-162067984-GAAAA-GAA

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