5-162102565-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_198903.2(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 (★★).

Frequency

Genomes: 𝑓 0.82 ( 51485 hom., cov: 31)
Exomes 𝑓: 0.81 ( 100373 hom. )

Consequence

GABRG2
NM_198903.2 missense

Scores

15

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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in the GABRG2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 2.9939 (below the threshold of 3.09). Trascript score misZ: 3.9088 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank MANE Protein UniProt
GABRG2NM_198904.4 linkc.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
GABRG2ENST00000639213.2 linkc.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.:
31
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.:
0
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.:
31
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 submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 19, 2018- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJul 15, 2024This 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 submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Epilepsy, childhood absence 2 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.89
T
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
N
LIST_S2
Benign
0.22
T;T
MetaRNN
Benign
0.0000016
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.44
T
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
T
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.

Other links and lift over

dbSNP: rs211035; hg19: chr5-161529571; COSMIC: COSV62715958; COSMIC: COSV62715958; API