5-162102565-A-G

Position:

chr5-162102565-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 12/17 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRG2. . Gene score misZ 2.9939 (greater than the threshold 3.09). Trascript score misZ 3.9088 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, Dravet syndrome, undetermined early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, developmental and epileptic encephalopathy, 74, febrile seizures, familial, 8, childhood epilepsy with centrotemporal spikes.

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 id 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/exons	MANE	UniProt
GABRG2	NM_198904.4 linkuse as main transcript	c.631+1248A>G		intron_variant		ENST00000639213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRG2	ENST00000639213.2 linkuse as main transcript	c.631+1248A>G		intron_variant		1	NM_198904.4	A1	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

GnomAD3 exomes

AF:

0.823

AC:

105667

AN:

128346

Hom.:

43659

AF XY:

0.820

AC XY:

57662

AN XY:

70296

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 SAS exome

AF:

0.841

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

Gnomad4 AFR exome

AF:

0.848

Gnomad4 AMR exome

AF:

0.892

Gnomad4 ASJ exome

AF:

0.769

Gnomad4 EAS exome

AF:

0.749

Gnomad4 SAS exome

AF:

0.840

Gnomad4 FIN exome

AF:

0.834

Gnomad4 NFE exome

AF:

0.796

Gnomad4 OTH exome

AF:

0.802

GnomAD4 genome

AF:

0.822

AC:

124981

AN:

152070

Hom.:

51485

Cov.:

AF XY:

0.824

AC XY:

61274

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.855

Gnomad4 AMR

AF:

0.855

Gnomad4 ASJ

AF:

0.769

Gnomad4 EAS

AF:

0.746

Gnomad4 SAS

AF:

0.850

Gnomad4 FIN

AF:

0.848

Gnomad4 NFE

AF:

0.798

Gnomad4 OTH

AF:

0.821

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 19, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Epilepsy, childhood absence 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.7

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

MutationTaster

Benign

1.0

P;P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over