rs1554504681

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr8-23007710-C-G
• chr8-23007710-C-T
• chr8-23007710-C-A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 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
• 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: 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-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_015178.3
• 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 ClinVar as Pathogenic. ClinVar VariationId is 545418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 870711.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOBTB2	NM_015178.3	MANE Select	c.1465C>G	p.Arg489Gly	missense	Exon 5 of 10	NP_055993.2	Q9BYZ6-1
	RHOBTB2	NM_001160036.2		c.1531C>G	p.Arg511Gly	missense	Exon 7 of 12	NP_001153508.1	Q9BYZ6-2
	RHOBTB2	NM_001160037.2		c.1486C>G	p.Arg496Gly	missense	Exon 5 of 10	NP_001153509.1	Q9BYZ6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOBTB2	ENST00000251822.7	TSL:1 MANE Select	c.1465C>G	p.Arg489Gly	missense	Exon 5 of 10	ENSP00000251822.7	Q9BYZ6-1
	RHOBTB2	ENST00000519685.5	TSL:1	c.1531C>G	p.Arg511Gly	missense	Exon 7 of 12	ENSP00000427926.1	Q9BYZ6-2
	RHOBTB2-AS1	ENST00000502083.2	TSL:1	n.616G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Developmental and epileptic encephalopathy, 64 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.050	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.28	T
Sift4G	Benign	0.097	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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554504681; hg19: chr8-22865223;