chr5-162102565-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_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 -17 ACMG points.

PM1
In a topological_domain Extracellular (size 233) in uniprot entity GBRG2_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_198903.2
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
Apr 19, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
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
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