rs267607014

Variant names:

• chr3-77596730-T-C
• rs267607014
• NM_001395656.1:c.2846T>C

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 6 publications found

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]

ROBO2 Gene-Disease associations (from GenCC):

• vesicoureteral reflux 2

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305342 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.2846T>C	p.Ile949Thr	missense_variant	Exon 20 of 28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1	c.2846T>C	p.Ile949Thr	missense_variant	Exon 20 of 28		NM_001395656.1	ENSP00000512738.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249520 AF XY: 0.0000148

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000211 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

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 20, 2020

Human Genetic Laboratory, University of Liege

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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.

Mar 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital anomaly of kidney and urinary tract Uncertain:1

Jan 09, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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	0.0	.;.;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	0.0	.;.;N;.;.
PhyloP100		7.5
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
Vest4		0.81
ClinPred		0.14	T
GERP RS		6.2
PromoterAI		0.0050	Neutral
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

Other links and lift over

dbSNP: rs267607014; hg19: chr3-77645881;