rs193920745

Positions:

• chr8-23006055-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_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
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.89

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOBTB2	NM_015178.3	c.392C>G	p.Pro131Arg	missense_variant	4/10	ENST00000251822.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOBTB2	ENST00000251822.7	c.392C>G	p.Pro131Arg	missense_variant	4/10	1	NM_015178.3	P2
	ENST00000523884.1	n.148+1329G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;.;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.2	.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.77
MutPred		0.70		.;.;.;Gain of solvent accessibility (P = 0.0411);
MVP		0.81
MPC		2.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.77
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs193920745; hg19: chr8-22863568; COSMIC: COSV52573575; COSMIC: COSV52573575;