Genetic Variant RHOBTB2:p.Asn488Asp (chr8-23007707-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_015178.3(RHOBTB2):c.1462A>G(p.Asn488Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

RHOBTB2
NM_015178.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.32

Publications

0 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_015178.3

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-23007707-A-G is Pathogenic according to our data. Variant chr8-23007707-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1462A>G	p.Asn488Asp	missense	Exon 5 of 10	NP_055993.2	Q9BYZ6-1
RHOBTB2	NM_001160036.2		c.1528A>G	p.Asn510Asp	missense	Exon 7 of 12	NP_001153508.1	Q9BYZ6-2
RHOBTB2	NM_001160037.2		c.1483A>G	p.Asn495Asp	missense	Exon 5 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.1462A>G	p.Asn488Asp	missense	Exon 5 of 10	ENSP00000251822.7	Q9BYZ6-1
RHOBTB2	ENST00000519685.5	TSL:1	c.1528A>G	p.Asn510Asp	missense	Exon 7 of 12	ENSP00000427926.1	Q9BYZ6-2
RHOBTB2-AS1	ENST00000502083.2	TSL:1	n.619T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 64 (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

0.0075

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

-0.022

MutationAssessor

Uncertain

2.6

PhyloP100

9.3

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.37

Sift

Benign

0.045

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.71

MutPred

0.32

Loss of MoRF binding (P = 0.0481)

MVP

0.81

MPC

1.4

ClinPred

0.98

GERP RS

4.8

Varity_R

0.34

gMVP

0.87

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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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