chr5-162068010-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2

The NM_198904.4(GABRG2):​c.11C>T​(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GABRG2
NM_198904.4 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.19
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.

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 3.9213 (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=0.07821554).
BP6
Variant 5-162068010-C-T is Benign according to our data. Variant chr5-162068010-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 205557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000132 (20/151640) while in subpopulation AFR AF= 0.000484 (20/41290). AF 95% confidence interval is 0.000321. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRG2NM_198904.4 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/10 ENST00000639213.2 NP_944494.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRG2ENST00000639213.2 linkuse as main transcriptc.11C>T p.Pro4Leu missense_variant 1/101 NM_198904.4 ENSP00000491909 A1P18507-2

Frequencies

GnomAD3 genomes
AF:
0.000132
AC:
20
AN:
151640
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
250926
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135584
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1460774
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726768
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000132
AC:
20
AN:
151640
Hom.:
0
Cov.:
31
AF XY:
0.0000946
AC XY:
7
AN XY:
73974
show subpopulations
Gnomad4 AFR
AF:
0.000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000155
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

GABRG2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 20, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 26, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 20, 2021- -
Epilepsy, childhood absence 2;C1969810:Febrile seizures, familial, 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 22, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
23
DANN
Benign
0.96
DEOGEN2
Benign
0.24
.;T;.;.;.;.;.
Eigen
Benign
-0.20
Eigen_PC
Benign
0.028
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.078
T;T;T;T;T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
0.81
L;L;.;.;L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.64
.;.;.;.;N;N;.
REVEL
Benign
0.15
Sift
Benign
0.090
.;.;.;.;T;T;.
Sift4G
Benign
0.17
.;.;.;.;T;T;.
Polyphen
0.0
B;B;.;.;.;.;.
Vest4
0.19, 0.17
MVP
0.49
MPC
0.075
ClinPred
0.023
T
GERP RS
5.1
Varity_R
0.12
gMVP
0.58

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: rs375295110; hg19: chr5-161495016; API