3-77580049-C-T

Position:

chr3-77580049-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001395656.1(ROBO2):c.2443C>T(p.Arg815Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00239 in 1,613,634 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 92 hom. )

Consequence

ROBO2
NM_001395656.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.99

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076765716).

BP6

Variant 3-77580049-C-T is Benign according to our data. Variant chr3-77580049-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224345.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO2	NM_001395656.1 linkuse as main transcript	c.2443C>T	p.Arg815Trp	missense_variant	17/28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1 linkuse as main transcript	c.2443C>T	p.Arg815Trp	missense_variant	17/28		NM_001395656.1	ENSP00000512738.1		A0A8Q3WLE3

Frequencies

GnomAD3 genomes

AF:

0.00425

AC:

646

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0356

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00925

AC:

2301

AN:

248880

Hom.:

AF XY:

0.00713

AC XY:

962

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.00187

Gnomad AMR exome

AF:

0.0598

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.00696

GnomAD4 exome

AF:

0.00220

AC:

3209

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1409

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.0579

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.00428

AC:

651

AN:

152084

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

342

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.0358

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000945

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.000532

Hom.:

Bravo

AF:

0.00743

ESP6500AA

AF:

0.00212

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.00712

AC:

860

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vesicoureteral reflux 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Congenital anomaly of kidney and urinary tract

Benign:1

Benign, criteria provided, single submitter

curation

Institute of Human Genetics, University of Leipzig Medical Center

Jan 09, 2021

This ROBO2 variant was reported as Uncertain Significance in PMID: 27657687 with original nomenclature reported as c.C2431T, p.R811W. Variant was re-classified as Benign based on the criteria PP3_Supporting, BA1_StandAlone. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

.;.;T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D;D;D

MetaRNN

Benign

0.0077

T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

.;.;M;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.5

D;.;D;D;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.0030

D;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0, 1.0

.;.;D;D;.

Vest4

0.66

MVP

0.72

MPC

0.77

ClinPred

0.038

GERP RS

4.6

Varity_R

0.40

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over