3-77040382-G-C

Variant names:

• chr3-77040382-G-C
• rs79942150
• NM_001395656.1:c.-404G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001395656.1(ROBO2):​c.-404G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00745 in 1,008,888 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (137 hom.)
• Consequence: ROBO2 NM_001395656.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.21
• 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, Labcorp Genetics (formerly Invitae)
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 3-77040382-G-C is Benign according to our data. Variant chr3-77040382-G-C is described in ClinVar as [Benign]. Clinvar id is 346670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.-404G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28	ENST00000696593.1	NP_001382585.1
ROBO2	NM_001395656.1	c.-404G>C		5_prime_UTR_variant	Exon 1 of 28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1	c.-404G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 28		NM_001395656.1	ENSP00000512738.1
ROBO2	ENST00000696593.1	c.-404G>C		5_prime_UTR_variant	Exon 1 of 28		NM_001395656.1	ENSP00000512738.1

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4975 AN: 152164 Hom.: 278 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.00294 AC: 2517 AN: 856606 Hom.: 137 Cov.: 33 AF XY: 0.00281 AC XY: 1116 AN XY: 396744

African (AFR) AF: 0.123 AC: 2009 AN: 16322

American (AMR) AF: 0.00568 AC: 13 AN: 2290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5766

East Asian (EAS) AF: 0.00219 AC: 10 AN: 4566

South Asian (SAS) AF: 0.0124 AC: 227 AN: 18290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1184

Middle Eastern (MID) AF: 0.00354 AC: 6 AN: 1694

European-Non Finnish (NFE) AF: 0.0000746 AC: 58 AN: 777882

Other (OTH) AF: 0.00678 AC: 194 AN: 28612

GnomAD4 genome AF: 0.0328 AC: 4995 AN: 152282 Hom.: 278 Cov.: 32 AF XY: 0.0326 AC XY: 2427 AN XY: 74470

African (AFR) AF: 0.113 AC: 4684 AN: 41548

American (AMR) AF: 0.0100 AC: 153 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00503 AC: 26 AN: 5172

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68020

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.000580 Hom.: 0

Bravo AF: 0.0364

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Vesicoureteral reflux 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		3.2
PromoterAI		0.0026	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs79942150; hg19: chr3-77089533;