rs966955210

Variant names:

• chr8-22994621-A-G
• rs966955210
• ENST00000519685.5:c.38A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001160036.2(RHOBTB2):​c.38A>G​(p.Lys13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: RHOBTB2 NM_001160036.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.339
• Publications: 0 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]

PEBP4 (HGNC:28319): (phosphatidylethanolamine binding protein 4) The phosphatidylethanolamine (PE)-binding proteins, including PEBP4, are an evolutionarily conserved family of proteins with pivotal biologic functions, such as lipid binding and inhibition of serine proteases (Wang et al., 2004 [PubMed 15302887]).[supplied by OMIM, Dec 2008]

RHOBTB2-AS1 (HGNC:58239):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0692842).
• BP6: Variant 8-22994621-A-G is Benign according to our data. Variant chr8-22994621-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1620762.Status of the report is criteria_provided_single_submitter, 1 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_001160036.2		c.38A>G	p.Lys13Arg	missense	Exon 3 of 12	NP_001153508.1	Q9BYZ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOBTB2	ENST00000519685.5	TSL:1	c.38A>G	p.Lys13Arg	missense	Exon 3 of 12	ENSP00000427926.1	Q9BYZ6-2
	RHOBTB2	ENST00000524077.5	TSL:3	c.38A>G	p.Lys13Arg	missense	Exon 3 of 6	ENSP00000430785.1	E5RI44
	RHOBTB2	ENST00000867414.1		c.-29A>G		5_prime_UTR	Exon 2 of 11	ENSP00000537473.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399180 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 690112

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49254

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078792

Other (OTH) AF: 0.0000172 AC: 1 AN: 57994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000380802), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.1
DANN	Benign	0.91
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.34
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.028
Sift	Benign	0.45	T
Sift4G	Benign	0.15	T
Vest4		0.050
MutPred		0.18		Loss of ubiquitination at K13 (P = 0.0056)
MVP		0.41
MPC		1.1
ClinPred		0.054	T
GERP RS		-1.8
gMVP		0.35
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs966955210; hg19: chr8-22852134;