8-23007627-G-C

Variant names:

• chr8-23007627-G-C
• rs1554504663
• NM_015178.3:c.1382G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_015178.3(RHOBTB2):​c.1382G>C​(p.Arg461Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R461H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOBTB2 NM_015178.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.91
• Publications: 0 publications found

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]

RHOBTB2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 64

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000245025 (HGNC:58239):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-23007627-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 545417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 8-23007627-G-C is Pathogenic according to our data. Variant chr8-23007627-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1515448.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOBTB2	NM_015178.3	c.1382G>C	p.Arg461Pro	missense_variant	Exon 5 of 10	ENST00000251822.7	NP_055993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000251822.7	c.1382G>C	p.Arg461Pro	missense_variant	Exon 5 of 10	1	NM_015178.3	ENSP00000251822.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 64 Pathogenic:1

Sep 01, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. A different missense change at the same codon (p.Arg461His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000545417 /PMID: 28856709). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Uncertain:1

Jul 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg483 amino acid residue in RHOBTB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28856709, 229276004). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RHOBTB2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 483 of the RHOBTB2 protein (p.Arg483Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Benign	0.0	.;.;M
PhyloP100		9.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.093	T;T;T
Vest4		0.92
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.73
gMVP		0.96
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1554504663; hg19: chr8-22865140;