Genetic Variant ROBO2:p.Val25Met (chr3-75937566-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001378191.1(ROBO2):c.73G>A(p.Val25Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V25V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ROBO2
NM_001378191.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 0.585

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0020155013).

BP6

Variant 3-75937566-G-A is Benign according to our data. Variant chr3-75937566-G-A is described in ClinVar as Benign. ClinVar VariationId is 518349.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378191.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROBO2	NM_001378191.1	c.73G>A	p.Val25Met	missense	Exon 2 of 30	NP_001365120.1	A0A8Q3SIW8
ROBO2	NM_001378190.1	c.73G>A	p.Val25Met	missense	Exon 2 of 29	NP_001365119.1
ROBO2	NM_001378195.1	c.73G>A	p.Val25Met	missense	Exon 2 of 29	NP_001365124.1	A0A8Q3SIU0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROBO2	ENST00000696630.1		c.73G>A	p.Val25Met	missense	Exon 2 of 30	ENSP00000512767.1	A0A8Q3SIW8
ROBO2	ENST00000696629.1		c.73G>A	p.Val25Met	missense	Exon 2 of 29	ENSP00000512766.1	A0A8Q3SIU0
ROBO2	ENST00000471893.2	TSL:4	c.73G>A	p.Val25Met	missense	Exon 2 of 29	ENSP00000418190.2	H7C4U9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.308

AC:

33746

AN:

109468

AF XY:

0.308

show subpopulations

Gnomad AFR exome

AF:

0.424

Gnomad AMR exome

AF:

0.205

Gnomad ASJ exome

AF:

0.311

Gnomad EAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.355

Gnomad NFE exome

AF:

0.361

Gnomad OTH exome

AF:

0.320

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.166

Hom.:

ExAC

AF:

0.382

AC:

44297

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Vesicoureteral reflux 2 (2)

ROBO2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.4

(source)

DANN

Benign

0.93

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.99

PhyloP100

0.58

PROVEAN

Benign

0.070

REVEL

Benign

0.016

Sift

Benign

0.093

Sift4G

Uncertain

0.051

Vest4

0.082

MPC

0.22

ClinPred

0.000046

GERP RS

2.0

gMVP

0.17

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over