chr8-23007710-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_015178.3(RHOBTB2):c.1465C>G(p.Arg489Gly) variant causes a missense change. 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. R489W) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
RHOBTB2
NM_015178.3 missense
NM_015178.3 missense
Scores
7
6
4
Clinical Significance
Conservation
PhyloP100: 4.00
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 16 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_015178.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-23007711-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 545418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, RHOBTB2
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823
PP5
Variant 8-23007710-C-G is Pathogenic according to our data. Variant chr8-23007710-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 870711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-23007710-C-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RHOBTB2 | NM_015178.3 | c.1465C>G | p.Arg489Gly | missense_variant | 5/10 | ENST00000251822.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RHOBTB2 | ENST00000251822.7 | c.1465C>G | p.Arg489Gly | missense_variant | 5/10 | 1 | NM_015178.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 38
GnomAD4 exome
Cov.:
38
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Developmental and epileptic encephalopathy, 64 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495261.11, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg489Gly) has been reported as pathogenic (ClinVar ID: VCV000870711.7, PM5). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67, 3Cnet: 0.963, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
1.0
.;.;D
Vest4
MutPred
0.49
.;.;Loss of MoRF binding (P = 0.0062);
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