Genetic Variant NM_198904.4:c.588C>T (chr5-162101274-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_198904.4(GABRG2):c.588C>T(p.Asn196Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,603,060 control chromosomes in the GnomAD database, including 58,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8328 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49878 hom. )

Consequence

GABRG2
NM_198904.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.38

Publications

75 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 5-162101274-C-T is Benign according to our data. Variant chr5-162101274-C-T is described in ClinVar as Benign. ClinVar VariationId is 93434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRG2	NM_198904.4	MANE Select	c.588C>T	p.Asn196Asn	synonymous	Exon 5 of 10	NP_944494.1	P18507-2
GABRG2	NM_198903.2		c.588C>T	p.Asn196Asn	synonymous	Exon 5 of 11	NP_944493.2	P18507-3
GABRG2	NM_001375343.1		c.588C>T	p.Asn196Asn	synonymous	Exon 5 of 10	NP_001362272.1	A0A1X7SBZ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GABRG2	ENST00000639213.2	TSL:1 MANE Select	c.588C>T	p.Asn196Asn	synonymous	Exon 5 of 10	ENSP00000491909.2	P18507-2
GABRG2	ENST00000414552.6	TSL:1	c.588C>T	p.Asn196Asn	synonymous	Exon 5 of 11	ENSP00000410732.2	P18507-3
GABRG2	ENST00000639111.2	TSL:1	c.588C>T	p.Asn196Asn	synonymous	Exon 5 of 9	ENSP00000492125.2	P18507-1

Frequencies

GnomAD3 genomes

AF:

0.315

AC:

47844

AN:

151852

Hom.:

8314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.435

Gnomad AMI

AF:

0.298

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.579

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.281

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.293

GnomAD2 exomes

AF:

0.284

AC:

71260

AN:

250782

AF XY:

0.278

show subpopulations

Gnomad AFR exome

AF:

0.437

Gnomad AMR exome

AF:

0.236

Gnomad ASJ exome

AF:

0.296

Gnomad EAS exome

AF:

0.605

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.242

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.252

AC:

365929

AN:

1451090

Hom.:

49878

Cov.:

AF XY:

0.251

AC XY:

181557

AN XY:

722312

show subpopulations

African (AFR)

AF:

0.434

AC:

14392

AN:

33154

American (AMR)

AF:

0.241

AC:

10754

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

7926

AN:

26046

East Asian (EAS)

AF:

0.563

AC:

22272

AN:

39554

South Asian (SAS)

AF:

0.218

AC:

18741

AN:

86074

European-Finnish (FIN)

AF:

0.284

AC:

15151

AN:

53330

Middle Eastern (MID)

AF:

0.238

AC:

1366

AN:

5742

European-Non Finnish (NFE)

AF:

0.235

AC:

258891

AN:

1102468

Other (OTH)

AF:

0.274

AC:

16436

AN:

60054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

11762

23524

35285

47047

58809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8878

17756

26634

35512

44390

<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:

0.315

AC:

47897

AN:

151970

Hom.:

8328

Cov.:

AF XY:

0.315

AC XY:

23413

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.435

AC:

18016

AN:

41428

American (AMR)

AF:

0.256

AC:

3915

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1042

AN:

3464

East Asian (EAS)

AF:

0.579

AC:

2989

AN:

5164

South Asian (SAS)

AF:

0.225

AC:

1086

AN:

4818

European-Finnish (FIN)

AF:

0.281

AC:

2969

AN:

10558

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16908

AN:

67956

Other (OTH)

AF:

0.295

AC:

619

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1623

3247

4870

6494

8117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.267

Hom.:

18872

Bravo

AF:

0.320

Asia WGS

AF:

0.366

AC:

1272

AN:

3478

EpiCase

AF:

0.245

EpiControl

AF:

0.236

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2 (1)

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2;C1969810:Febrile seizures, familial, 8 (1)

Febrile seizures, familial, 8 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.2

(source)

DANN

Benign

0.65

PhyloP100

1.4

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over