NM_000814.6:c.650G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217C) has been classified as Uncertain significance.

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 -3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000814.6
PP2
Missense variant in the GABRB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 3.3856 (above the threshold of 3.09). Trascript score misZ: 4.4544 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank MANE Protein UniProt
GABRB3NM_000814.6 linkc.650G>A p.Arg217His missense_variant Exon 6 of 9 ENST00000311550.10 NP_000805.1 P28472-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GABRB3ENST00000311550.10 linkc.650G>A p.Arg217His missense_variant Exon 6 of 9 1 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
Mar 25, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Mar 10, 2020
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SUDDEN INFANT DEATH SYNDROME Uncertain:1
Oct 01, 2021
Robert's Program, Boston Children's Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

We 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
Aug 01, 2002
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5 Benign:1
Jan 19, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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