rs121913125

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000814.6(GABRB3):​c.650G>A​(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GABRB3
NM_000814.6 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.71
Variant links:
Genes affected
GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRB3. . Gene score misZ 3.3856 (greater than the threshold 3.09). Trascript score misZ 4.4544 (greater than threshold 3.09). GenCC has associacion of gene with childhood absence epilepsy, developmental and epileptic encephalopathy, 43, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, epilepsy, childhood absence, susceptibility to, 5.
BP4
Computational evidence support a benign effect (MetaRNN=0.123971224).
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GABRB3NM_000814.6 linkuse as main transcriptc.650G>A p.Arg217His missense_variant 6/9 ENST00000311550.10 NP_000805.1 P28472-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GABRB3ENST00000311550.10 linkuse as main transcriptc.650G>A p.Arg217His missense_variant 6/91 NM_000814.6 ENSP00000308725.5 P28472-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251428
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.0000303
AC XY:
22
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152264
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 43 Uncertain:2
Uncertain significance, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 10, 2020- -
SUDDEN INFANT DEATH SYNDROME Uncertain:1
Uncertain significance, criteria provided, single submitterresearchRobert's Program, Boston Children's HospitalOct 01, 2021We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. -
Insomnia Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyOMIMAug 01, 2002- -
Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
28
DANN
Benign
0.94
DEOGEN2
Benign
0.35
.;T;.;.;.;.;.;.;.
Eigen
Benign
-0.050
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.93
.;D;D;D;D;.;D;D;.
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.4
.;L;.;.;L;.;.;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-2.1
.;N;.;N;N;.;.;N;N
REVEL
Benign
0.21
Sift
Benign
0.38
.;T;.;T;T;.;.;T;T
Sift4G
Benign
0.66
T;T;T;T;T;.;.;T;T
Polyphen
0.036, 0.22, 0.029
.;B;.;B;B;.;.;.;.
Vest4
0.48
MVP
0.65
MPC
2.4
ClinPred
0.12
T
GERP RS
5.3
Varity_R
0.20
gMVP
0.61

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: rs121913125; hg19: chr15-26825498; API