8-23007707-A-G

Position:

• chr8-23007707-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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]

ENSG00000245025 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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.
• PP5: Variant 8-23007707-A-G is Pathogenic according to our data. Variant chr8-23007707-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-23007707-A-G is described in Lovd as [Pathogenic]. Variant chr8-23007707-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOBTB2	NM_015178.3	c.1462A>G	p.Asn488Asp	missense_variant	5/10	ENST00000251822.7	NP_055993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000251822.7	c.1462A>G	p.Asn488Asp	missense_variant	5/10	1	NM_015178.3	ENSP00000251822.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 64 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for Epileptic encephalopathy, early infantile, 64, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29276004). PM1-Supporting => PM1 downgraded in strength to Supporting. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 17, 2020	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.045	D;T;T
Sift4G	Uncertain	0.024	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.71
MutPred		0.32		.;.;Loss of MoRF binding (P = 0.0481);
MVP		0.81
MPC		1.4
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.34
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs1554504678; hg19: chr8-22865220;