Genetic Variant GABRG2:c.-375G>C (chr5-162067625-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001375347.1(GABRG2):c.4G>C(p.Asp2His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 496,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

GABRG2
NM_001375347.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.59

Publications

0 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: Ambry Genetics, G2P, 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026697993).

BP6

Variant 5-162067625-G-C is Benign according to our data. Variant chr5-162067625-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2571239.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00107 (163/152128) while in subpopulation AFR AF = 0.00357 (148/41512). AF 95% confidence interval is 0.0031. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 163 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375347.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRG2	NM_001375347.1	c.4G>C	p.Asp2His	missense	Exon 1 of 10	NP_001362276.1	A0A1W2PQR9
GABRG2	NM_001375343.1	c.-375G>C		5_prime_UTR	Exon 1 of 10	NP_001362272.1	A0A1X7SBZ8
GABRG2	NM_001375344.1	c.-375G>C		5_prime_UTR	Exon 1 of 11	NP_001362273.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRG2	ENST00000639111.2	TSL:1	c.-375G>C		5_prime_UTR	Exon 1 of 9	ENSP00000492125.2	P18507-1
GABRG2	ENST00000640985.1	TSL:5	c.4G>C	p.Asp2His	missense	Exon 1 of 10	ENSP00000492293.1	A0A1W2PQR9
GABRG2	ENST00000943443.1		c.-375G>C		5_prime_UTR	Exon 1 of 10	ENSP00000613502.1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000163

AC:

AN:

344474

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

176646

show subpopulations

African (AFR)

AF:

0.00386

AC:

AN:

10372

American (AMR)

AF:

0.000508

AC:

AN:

11802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11474

East Asian (EAS)

AF:

0.00

AC:

AN:

28034

South Asian (SAS)

AF:

0.00

AC:

AN:

18156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24776

Middle Eastern (MID)

AF:

0.000606

AC:

AN:

1650

European-Non Finnish (NFE)

AF:

0.00000922

AC:

AN:

216840

Other (OTH)

AF:

0.000328

AC:

AN:

21370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152128

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00357

AC:

148

AN:

41512

American (AMR)

AF:

0.000786

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67992

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000498

Hom.:

Bravo

AF:

0.00113

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.0

(source)

DANN

Benign

0.70

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.25

MetaRNN

Benign

0.027

PhyloP100

1.6

GERP RS

4.1

PromoterAI

-0.0096

Neutral

(source)

Mutation Taster

=299/1

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