8-23007710-C-G

Variant names:

• chr8-23007710-C-G
• rs1554504681
• NM_015178.3:c.1465C>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_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. R489Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOBTB2 NM_015178.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ENSG00000245025 (HGNC:58239):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-23007711-G-A is described in Lovd as [Pathogenic].
• 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 rank	MANE	Protein	UniProt
RHOBTB2	NM_015178.3	c.1465C>G	p.Arg489Gly	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.1465C>G	p.Arg489Gly	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 64 Pathogenic:1

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Uncertain	2.4	.;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.097	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.79
MutPred		0.49		.;.;Loss of MoRF binding (P = 0.0062);
MVP		0.88
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.93

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

Other links and lift over

dbSNP: rs1554504681; hg19: chr8-22865223;