rs267607014

Positions:

• chr3-77596730-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001395656.1(ROBO2):​c.2846T>C​(p.Ile949Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: ROBO2 NM_001395656.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 7.45

Genes affected

ROBO2 (HGNC:10250): (roundabout guidance receptor 2) The protein encoded by this gene belongs to the ROBO family, part of the immunoglobulin superfamily of proteins that are highly conserved from fly to human. The encoded protein is a transmembrane receptor for the slit homolog 2 protein and functions in axon guidance and cell migration. Mutations in this gene are associated with vesicoureteral reflux, characterized by the backward flow of urine from the bladder into the ureters or the kidney. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25206137).
• BS2: High AC in GnomAdExome4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.2846T>C	p.Ile949Thr	missense_variant	20/28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1	c.2846T>C	p.Ile949Thr	missense_variant	20/28		NM_001395656.1	ENSP00000512738.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249520 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461684 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000306 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vesicoureteral reflux 2 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Human Genetic Laboratory, University of Liege	Feb 20, 2020	The variant is in a gene (ROBO2) previously associated with CAKUT in human. However, ROBO2 has never been associated with uterine malformations. This missense variant is present in a very low frequency in Gnomad (MAF:0.00001219). There is conflicting predictions among in silico prediction tools.We have identified this variant in heterozygous state in a fetus with bilateral renal anomalies and uterovaginal aplasia, the unaffected mother, the maternal aunt with unilateral renal agenesis and MRKH syndrome type 2, and a maternal cousin with unilateral renal agenesis and MRKH syndrome type 2. The observed mode of inheritance was autosomal dominant with incomplete penetrance. A pathogenic variant in the gene GREB1L was also shared by all the relatives. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2007	- -

Congenital anomaly of kidney and urinary tract Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Institute of Human Genetics, University of Leipzig Medical Center

Jan 09, 2021

This ROBO2 variant was reported as Likely pathogenic​ in PMID: 17357069 with original nomenclature reported as c.3477T->C, I945T . Variant was re-classified as Uncertain Significance based on the criteria PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Benign	0.28
DEOGEN2	Benign	0.075	.;.;T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	0.0038
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	.;.;N;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.27	N;.;N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.27	T;.;T;T;.
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.0	.;.;B;B;.
Vest4		0.81
MutPred		0.50		.;.;Gain of disorder (P = 0.0177);Gain of disorder (P = 0.0177);.;
MVP		0.85
MPC		0.28
ClinPred		0.14	T
GERP RS		6.2
Varity_R		0.16
gMVP		0.45

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: rs267607014; hg19: chr3-77645881;