8-23007600-C-G

Position:

• chr8-23007600-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_015178.3(RHOBTB2):​c.1355C>G​(p.Ala452Gly) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHOBTB2 NM_015178.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.84

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_015178.3
• 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, 0.753
• PP5: Variant 8-23007600-C-G is Pathogenic according to our data. Variant chr8-23007600-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545421.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-23007600-C-G is described in Lovd as [Likely_pathogenic]. Variant chr8-23007600-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOBTB2	NM_015178.3	c.1355C>G	p.Ala452Gly	missense_variant	5/10	ENST00000251822.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOBTB2	ENST00000251822.7	c.1355C>G	p.Ala452Gly	missense_variant	5/10	1	NM_015178.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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). PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 17, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.070	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.72
MutPred		0.75		.;.;Gain of loop (P = 0.0435);
MVP		0.52
MPC		1.3
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.77
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554504656; hg19: chr8-22865113;