5-162102565-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000414552.6(GABRG2):c.643A>G(p.Ile215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 454,032 control chromosomes in the GnomAD database, including 151,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I215L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.82 ( 51485 hom., cov: 31)

Exomes 𝑓: 0.81 ( 100373 hom. )

Consequence

GABRG2
ENST00000414552.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.00

Publications

20 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5540011E-6).

BP6

Variant 5-162102565-A-G is Benign according to our data. Variant chr5-162102565-A-G is described in ClinVar as Benign. ClinVar VariationId is 585903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRG2	NM_198904.4 link	c.631+1248A>G		intron_variant	Intron 5 of 9	ENST00000639213.2	NP_944494.1	P18507-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRG2	ENST00000639213.2 link	c.631+1248A>G		intron_variant	Intron 5 of 9	1	NM_198904.4	ENSP00000491909.2		P18507-2

Frequencies

GnomAD3 genomes

AF:

0.822

AC:

124892

AN:

151948

Hom.:

51453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.855

Gnomad AMI

AF:

0.742

Gnomad AMR

AF:

0.855

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.746

Gnomad SAS

AF:

0.851

Gnomad FIN

AF:

0.848

Gnomad MID

AF:

0.792

Gnomad NFE

AF:

0.798

Gnomad OTH

AF:

0.820

GnomAD2 exomes

AF:

0.823

AC:

105667

AN:

128346

AF XY:

0.820

show subpopulations

Gnomad AFR exome

AF:

0.852

Gnomad AMR exome

AF:

0.894

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.755

Gnomad FIN exome

AF:

0.840

Gnomad NFE exome

AF:

0.799

Gnomad OTH exome

AF:

0.799

GnomAD4 exome

AF:

0.814

AC:

245848

AN:

301962

Hom.:

100373

Cov.:

AF XY:

0.814

AC XY:

140140

AN XY:

172066

show subpopulations

African (AFR)

AF:

0.848

AC:

7264

AN:

8562

American (AMR)

AF:

0.892

AC:

24319

AN:

27276

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

8293

AN:

10786

East Asian (EAS)

AF:

0.749

AC:

6897

AN:

9204

South Asian (SAS)

AF:

0.840

AC:

50089

AN:

59640

European-Finnish (FIN)

AF:

0.834

AC:

10311

AN:

12356

Middle Eastern (MID)

AF:

0.769

AC:

931

AN:

1210

European-Non Finnish (NFE)

AF:

0.796

AC:

126465

AN:

158870

Other (OTH)

AF:

0.802

AC:

11279

AN:

14058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

2541

5081

7622

10162

12703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.822

AC:

124981

AN:

152070

Hom.:

51485

Cov.:

AF XY:

0.824

AC XY:

61274

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.855

AC:

35445

AN:

41478

American (AMR)

AF:

0.855

AC:

13048

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2671

AN:

3472

East Asian (EAS)

AF:

0.746

AC:

3848

AN:

5160

South Asian (SAS)

AF:

0.850

AC:

4093

AN:

4816

European-Finnish (FIN)

AF:

0.848

AC:

8965

AN:

10578

Middle Eastern (MID)

AF:

0.789

AC:

232

AN:

294

European-Non Finnish (NFE)

AF:

0.798

AC:

54277

AN:

67994

Other (OTH)

AF:

0.821

AC:

1725

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1135

2270

3404

4539

5674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.781

Hom.:

5455

Bravo

AF:

0.824

TwinsUK

AF:

0.801

AC:

2970

ALSPAC

AF:

0.806

AC:

3105

ExAC

AF:

0.793

AC:

10420

Asia WGS

AF:

0.811

AC:

2824

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported. -

Developmental and epileptic encephalopathy, 74

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.7

(source)

DANN

Benign

0.13

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.000030

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-1.0

PhyloP100

-1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.020

N;.

REVEL

Benign

0.029

Sift

Benign

0.99

T;.

Sift4G

Benign

0.13

T;.

Vest4

0.024

MPC

1.1

ClinPred

0.00014

GERP RS

0.23

gMVP

0.20

Mutation Taster

=100/0

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over