3-77580049-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R815Q) has been classified as Likely benign.

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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

vesicoureteral reflux 2
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
familial vesicoureteral reflux
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ROBO2 links:

ENSG00000305342 (HGNC:):

ENSG00000305342 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 224345.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395656.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROBO2	NM_001395656.1	MANE Select	c.2443C>T	p.Arg815Trp	missense	Exon 17 of 28	NP_001382585.1	A0A8Q3WLE3
ROBO2	NM_001394212.1		c.2500C>T	p.Arg834Trp	missense	Exon 16 of 28	NP_001381141.1
ROBO2	NM_001378191.1		c.2491C>T	p.Arg831Trp	missense	Exon 18 of 30	NP_001365120.1	A0A8Q3SIW8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROBO2	ENST00000696593.1	MANE Select	c.2443C>T	p.Arg815Trp	missense	Exon 17 of 28	ENSP00000512738.1	A0A8Q3WLE3
ROBO2	ENST00000461745.5	TSL:1	c.2431C>T	p.Arg811Trp	missense	Exon 16 of 26	ENSP00000417164.1	Q9HCK4-1
ROBO2	ENST00000473767.5	TSL:1	n.*875C>T		non_coding_transcript_exon	Exon 17 of 27	ENSP00000418117.1	F8WBR3

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

GnomAD2 exomes

AF:

0.00925

AC:

2301

AN:

248880

AF XY:

0.00713

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 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

African (AFR)

AF:

0.00117

AC:

AN:

33472

American (AMR)

AF:

0.0579

AC:

2591

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000765

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00155

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000231

AC:

257

AN:

1111764

Other (OTH)

AF:

0.00285

AC:

172

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

195

391

586

782

977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00428

AC:

651

AN:

152084

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

342

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41490

American (AMR)

AF:

0.0358

AC:

546

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000945

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67998

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00160

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Vesicoureteral reflux 2 (2)

Congenital anomaly of kidney and urinary tract (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

PhyloP100

4.0

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.39

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

1.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over