3-75937512-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001378191.1(ROBO2):​c.19C>T​(p.Arg7Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000986 in 1,419,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: ROBO2 NM_001378191.1 missense
• Clinical Significance: Not reported in ClinVar
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.094400406).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

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>T	p.Arg7Cys	missense	Exon 2 of 30	NP_001365120.1	A0A8Q3SIW8
	ROBO2	NM_001378190.1		c.19C>T	p.Arg7Cys	missense	Exon 2 of 29	NP_001365119.1
	ROBO2	NM_001378195.1		c.19C>T	p.Arg7Cys	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>T	p.Arg7Cys	missense	Exon 2 of 30	ENSP00000512767.1	A0A8Q3SIW8
	ROBO2	ENST00000696629.1		c.19C>T	p.Arg7Cys	missense	Exon 2 of 29	ENSP00000512766.1	A0A8Q3SIU0
	ROBO2	ENST00000471893.2	TSL:4	c.19C>T	p.Arg7Cys	missense	Exon 2 of 29	ENSP00000418190.2	H7C4U9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 226762 AF XY: 0.0000159

Gnomad AFR exome AF: 0.0000724

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000986 AC: 14 AN: 1419592 Hom.: 0 Cov.: 29 AF XY: 0.0000114 AC XY: 8 AN XY: 704832

African (AFR) AF: 0.0000302 AC: 1 AN: 33096

American (AMR) AF: 0.0000475 AC: 2 AN: 42136

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

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39070

South Asian (SAS) AF: 0.0000123 AC: 1 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: 0.00000274 AC: 3 AN: 1096662

Other (OTH) AF: 0.0000338 AC: 2 AN: 59206

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000717 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.94
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.54
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.035
Sift	Benign	0.065	T
Sift4G	Uncertain	0.025	D
Vest4		0.25
MutPred		0.56		Gain of glycosylation at T9 (P = 0.0069)
MVP		0.068
MPC		0.30
ClinPred		0.043	T
GERP RS		0.34
gMVP		0.78

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;