rs1554504684

Variant names:

• chr8-23007711-G-A
• rs1554504684
• NM_015178.3:c.1466G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-23007711-G-A
• chr8-23007711-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001160036.2(RHOBTB2):​c.1532G>A​(p.Arg511Gln) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOBTB2 NM_001160036.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.15
• Publications: 1 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

RHOBTB2-AS1 (HGNC:58239):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001160036.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-23007710-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 870711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 8-23007711-G-A is Pathogenic according to our data. Variant chr8-23007711-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 545418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160036.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOBTB2	NM_015178.3	MANE Select	c.1466G>A	p.Arg489Gln	missense	Exon 5 of 10	NP_055993.2
	RHOBTB2	NM_001160036.2		c.1532G>A	p.Arg511Gln	missense	Exon 7 of 12	NP_001153508.1
	RHOBTB2	NM_001160037.2		c.1487G>A	p.Arg496Gln	missense	Exon 5 of 10	NP_001153509.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOBTB2	ENST00000251822.7	TSL:1 MANE Select	c.1466G>A	p.Arg489Gln	missense	Exon 5 of 10	ENSP00000251822.7
	RHOBTB2	ENST00000519685.5	TSL:1	c.1532G>A	p.Arg511Gln	missense	Exon 7 of 12	ENSP00000427926.1
	RHOBTB2-AS1	ENST00000502083.2	TSL:1	n.615C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Developmental and epileptic encephalopathy, 64 (6)
3	-	-	not provided (3)
1	-	-	Chorea;C0013421:Dystonic disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.47
Sift	Benign	0.094	T
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.47		Loss of MoRF binding (P = 0.0132)
MVP		0.73
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.85
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1554504684; hg19: chr8-22865224; COSMIC: COSV52572914; COSMIC: COSV52572914;