3-75937512-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 11/15 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO2	NM_001378191.1	c.19C>T	p.Arg7Cys	missense_variant	Exon 2 of 30		NP_001365120.1
ROBO2	NM_001378190.1	c.19C>T	p.Arg7Cys	missense_variant	Exon 2 of 29		NP_001365119.1
ROBO2	NM_001378195.1	c.19C>T	p.Arg7Cys	missense_variant	Exon 2 of 29		NP_001365124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696630.1	c.19C>T	p.Arg7Cys	missense_variant	Exon 2 of 30			ENSP00000512767.1
ROBO2	ENST00000696629.1	c.19C>T	p.Arg7Cys	missense_variant	Exon 2 of 29			ENSP00000512766.1
ROBO2	ENST00000471893.2	c.19C>T	p.Arg7Cys	missense_variant	Exon 2 of 29	4		ENSP00000418190.2

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000475

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000274

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000717 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	-0.34	N;.
REVEL	Benign	0.035
Sift	Benign	0.065	T;.
Sift4G	Uncertain	0.025	D;D
Vest4		0.25
MutPred		0.56		Gain of glycosylation at T9 (P = 0.0069);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

Publications

LitVar

Other links and lift over

dbSNP: rs12171318; hg19: chr3-75986663;