rs747011633

chr3-75937590-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2 PM4 BP6 BS2

The NM_001378191.1(ROBO2):c.97G>T(p.Gly33Ter) variant causes a stop gained change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROBO2 NM_001378191.1 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.00

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001378191.1 Downstream stopcodon found after 1630 codons.
• BP6: Variant 3-75937590-G-T is Benign according to our data. Variant chr3-75937590-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr3-75937590-G-T is described in Lovd as [Benign].
• BS2: High AC in GnomAdExome at 3534 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO2	NM_001378191.1	c.97G>T	p.Gly33Ter	stop_gained	2/30
ROBO2	NM_001378190.1	c.97G>T	p.Gly33Ter	stop_gained	2/29
ROBO2	NM_001378195.1	c.97G>T	p.Gly33Ter	stop_gained	2/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO2	ENST00000696630.1	c.97G>T	p.Gly33Ter	stop_gained	2/30
ROBO2	ENST00000696629.1	c.97G>T	p.Gly33Ter	stop_gained	2/29
ROBO2	ENST00000471893.2	c.97G>T	p.Gly33Ter	stop_gained	2/29	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0195 AC: 3534 AN: 181206 Hom.: 0 AF XY: 0.0197 AC XY: 1962 AN XY: 99442

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.0000573

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0226

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1403380 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 695790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.124 Hom.: 0

ExAC AF: 0.0736 AC: 8607

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Vesicoureteral reflux 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

ROBO2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	40
Dann	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.82	D
Vest4		0.50
GERP RS		4.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs747011633; hg19: chr3-75986741; COSMIC: COSV72213580;