Genetic Variant NM_015178.3:c.392C>G (chr8-23006055-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015178.3(RHOBTB2):c.392C>G(p.Pro131Arg) 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 Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. P131P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RHOBTB2
NM_015178.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.89

Publications

1 publications found

Variant links:

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: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 64
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

RHOBTB2 links:

RHOBTB2-AS1 (HGNC:58239):

RHOBTB2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015178.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHOBTB2	NM_015178.3	MANE Select	c.392C>G	p.Pro131Arg	missense	Exon 4 of 10	NP_055993.2	Q9BYZ6-1
RHOBTB2	NM_001160036.2		c.458C>G	p.Pro153Arg	missense	Exon 6 of 12	NP_001153508.1	Q9BYZ6-2
RHOBTB2	NM_001160037.2		c.413C>G	p.Pro138Arg	missense	Exon 4 of 10	NP_001153509.1	Q9BYZ6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RHOBTB2	ENST00000251822.7	TSL:1 MANE Select	c.392C>G	p.Pro131Arg	missense	Exon 4 of 10	ENSP00000251822.7	Q9BYZ6-1
RHOBTB2	ENST00000519685.5	TSL:1	c.458C>G	p.Pro153Arg	missense	Exon 6 of 12	ENSP00000427926.1	Q9BYZ6-2
RHOBTB2	ENST00000692529.1		c.419C>G	p.Pro140Arg	missense	Exon 4 of 10	ENSP00000509630.1	A0A8I5KV41

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.2

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.77

MutPred

0.70

Gain of solvent accessibility (P = 0.0411)

MVP

0.81

MPC

2.6

ClinPred

0.99

GERP RS

5.4

Varity_R

0.77

gMVP

0.92

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over