chr8-23007627-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong
The ENST00000251822.7(RHOBTB2):c.1382G>A(p.Arg461His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R461C) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
RHOBTB2
ENST00000251822.7 missense
ENST00000251822.7 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 9.91
Genes affected
RHOBTB2 (HGNC:18756): (Rho related BTB domain containing 2) The protein encoded by this gene is a small Rho GTPase and a candidate tumor suppressor. The encoded protein interacts with the cullin-3 protein, a ubiquitin E3 ligase necessary for mitotic cell division. This protein inhibits the growth and spread of some types of breast cancer. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RHOBTB2. . Gene score misZ 2.6599 (greater than the threshold 3.09). Trascript score misZ 3.127 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 64.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827
PP5
Variant 8-23007627-G-A is Pathogenic according to our data. Variant chr8-23007627-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-23007627-G-A is described in Lovd as [Pathogenic]. Variant chr8-23007627-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-23007627-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RHOBTB2 | NM_015178.3 | c.1382G>A | p.Arg461His | missense_variant | 5/10 | ENST00000251822.7 | NP_055993.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RHOBTB2 | ENST00000251822.7 | c.1382G>A | p.Arg461His | missense_variant | 5/10 | 1 | NM_015178.3 | ENSP00000251822 | P2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 38
GnomAD4 exome
Cov.:
38
GnomAD4 genome
GnomAD4 genome
Cov.:
32
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 64 Pathogenic:8
| Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Pathogenic, for Epileptic encephalopathy, early infantile, 64, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Dec 03, 2018 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Nov 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.1382G>Ap.Arg461His variant in RHOBTB2 gene has been reported previously in heterozygous state in individuals affected with Developmental and Epileptic Encephalopathy Straub J et al., 2018. Experimental studies have shown that this missense change affects RHOBTB2 function Straub J et al., 2018. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 461 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg461His in RHOBTB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 18, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 64 (MIM#618004). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) in the first BTB domain (PMID: 29276004). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant (often referred to as p.(Arg483His) in an alternative transcript) that has previously been identified in multiple de novo individuals with developmental and epileptic encephalopathy 64 (MIM#618004) (ClinVar, DECIPHER, PMID: 29276004). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2023 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28856709, 33098801, 33619735, 32653842, 29276004, 29768694, 32337345, 35872528, 35586607, 35231114, 34356170, 31957018) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 05, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RHOBTB2 function (PMID: 29276004). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RHOBTB2 protein function. ClinVar contains an entry for this variant (Variation ID: 545417). This missense change has been observed in individual(s) with RHOBTB2-related conditions (PMID: 28856709, 29276004). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 483 of the RHOBTB2 protein (p.Arg483His). - |
Inborn genetic diseases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
1.0
.;.;D
Vest4
MutPred
0.49
.;.;Loss of solvent accessibility (P = 0.0674);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at