chr3-75937512-C-A

Variant names:

• chr3-75937512-C-A
• rs12171318
• NM_001378191.1:c.19C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001378191.1(ROBO2):​c.19C>A​(p.Arg7Ser) 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROBO2 NM_001378191.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.539
• Publications: 2 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, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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=0.0021585822).
• BP6: Variant 3-75937512-C-A is Benign according to our data. Variant chr3-75937512-C-A is described in ClinVar as Benign. ClinVar VariationId is 518348.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	NM_001378191.1		c.19C>A	p.Arg7Ser	missense	Exon 2 of 30	NP_001365120.1	A0A8Q3SIW8
	ROBO2	NM_001378190.1		c.19C>A	p.Arg7Ser	missense	Exon 2 of 29	NP_001365119.1
	ROBO2	NM_001378195.1		c.19C>A	p.Arg7Ser	missense	Exon 2 of 29	NP_001365124.1	A0A8Q3SIU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	ENST00000696630.1		c.19C>A	p.Arg7Ser	missense	Exon 2 of 30	ENSP00000512767.1	A0A8Q3SIW8
	ROBO2	ENST00000696629.1		c.19C>A	p.Arg7Ser	missense	Exon 2 of 29	ENSP00000512766.1	A0A8Q3SIU0
	ROBO2	ENST00000471893.2	TSL:4	c.19C>A	p.Arg7Ser	missense	Exon 2 of 29	ENSP00000418190.2	H7C4U9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.500 AC: 113387 AN: 226762 AF XY: 0.500

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.500

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.500

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1419592 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 704832

African (AFR) AF: 0.00 AC: 0 AN: 33096

American (AMR) AF: 0.00 AC: 0 AN: 42136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25526

East Asian (EAS) AF: 0.00 AC: 0 AN: 39070

South Asian (SAS) AF: 0.00 AC: 0 AN: 81422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096662

Other (OTH) AF: 0.00 AC: 0 AN: 59206

GnomAD4 genome Cov.: 32

Alfa AF: 0.242 Hom.: 0

ExAC AF: 0.497 AC: 57339

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	Vesicoureteral reflux 2 (2)
-	-	1	ROBO2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.24
DANN	Benign	0.57
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.54
PROVEAN	Benign	0.43	N
REVEL	Benign	0.014
Sift	Benign	0.93	T
Sift4G	Benign	0.48	T
Vest4		0.064
MPC		0.25
ClinPred		0.0038	T
GERP RS		0.34
gMVP		0.73

Splicing

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

Other links and lift over

dbSNP: rs12171318; hg19: chr3-75986663; COSMIC: COSV72217800;