rs267607014

Variant names:

• chr3-77596730-T-C
• rs267607014
• NM_001395656.1:c.2846T>C

Variant summary

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

The NM_001395656.1(ROBO2):​c.2846T>C​(p.Ile949Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: ROBO2 NM_001395656.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 7.45
• Publications: 6 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, Labcorp Genetics (formerly Invitae)
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305342 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25206137).
• BS2: High AC in GnomAdExome4 at 57 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	NM_001395656.1	MANE Select	c.2846T>C	p.Ile949Thr	missense	Exon 20 of 28	NP_001382585.1
	ROBO2	NM_001394212.1		c.2903T>C	p.Ile968Thr	missense	Exon 19 of 28	NP_001381141.1
	ROBO2	NM_001378191.1		c.2894T>C	p.Ile965Thr	missense	Exon 21 of 30	NP_001365120.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	ENST00000696593.1	MANE Select	c.2846T>C	p.Ile949Thr	missense	Exon 20 of 28	ENSP00000512738.1
	ROBO2	ENST00000461745.5	TSL:1	c.2834T>C	p.Ile945Thr	missense	Exon 19 of 26	ENSP00000417164.1
	ROBO2	ENST00000490991.5	TSL:1	c.302T>C	p.Ile101Thr	missense	Exon 3 of 6	ENSP00000418344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249520 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461684 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000211 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	2	-	Vesicoureteral reflux 2 (3)
-	1	-	Congenital anomaly of kidney and urinary tract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Benign	0.28
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.29
Eigen_PC	Benign	0.0038
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		7.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.31
Sift	Benign	0.27	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.81
MutPred		0.50		Gain of disorder (P = 0.0177)
MVP		0.85
MPC		0.28
ClinPred		0.14	T
GERP RS		6.2
PromoterAI		0.0050	Neutral
Varity_R		0.16
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267607014; hg19: chr3-77645881;