chr4-20253941-C-A

Variant names:

• chr4-20253941-C-A
• rs200103892
• NM_004787.4:c.126C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004787.4(SLIT2):​c.126C>A​(p.His42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,694 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLIT2 NM_004787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

Genes affected

SLIT2 (HGNC:11086): (slit guidance ligand 2) This gene encodes a member of the slit family of secreted glycoproteins, which are ligands for the Robo family of immunoglobulin receptors. Slit proteins play highly conserved roles in axon guidance and neuronal migration and may also have functions during other cell migration processes including leukocyte migration. Members of the slit family are characterized by an N-terminal signal peptide, four leucine-rich repeats, nine epidermal growth factor repeats, and a C-terminal cysteine knot. Proteolytic processing of this protein gives rise to an N-terminal fragment that contains the four leucine-rich repeats and five epidermal growth factor repeats and a C-terminal fragment that contains four epidermal growth factor repeats and the cysteine knot. Both full length and cleaved proteins are secreted extracellularly and can function in axon repulsion as well as other specific processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

SLIT2 Gene-Disease associations (from GenCC):

• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004787.4. 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
	SLIT2	NM_004787.4	MANE Select	c.126C>A	p.His42Gln	missense	Exon 1 of 37	NP_004778.1	O94813-1
	SLIT2	NM_001289135.3		c.126C>A	p.His42Gln	missense	Exon 1 of 37	NP_001276064.1	O94813-2
	SLIT2	NM_001289136.3		c.126C>A	p.His42Gln	missense	Exon 1 of 36	NP_001276065.1	O94813-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT2	ENST00000504154.6	TSL:1 MANE Select	c.126C>A	p.His42Gln	missense	Exon 1 of 37	ENSP00000422591.1	O94813-1
	SLIT2	ENST00000503837.5	TSL:1	c.126C>A	p.His42Gln	missense	Exon 1 of 37	ENSP00000422261.1	O94813-2
	SLIT2	ENST00000503823.5	TSL:1	c.126C>A	p.His42Gln	missense	Exon 1 of 36	ENSP00000427548.1	O94813-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450694 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722086

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111898

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.094
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.68	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.73
Sift	Benign	0.096	T
Sift4G	Benign	0.49	T
Polyphen		0.54	P
Vest4		0.67
MutPred		0.59		Loss of glycosylation at S37 (P = 0.0695)
MVP		0.87
MPC		1.0
ClinPred		0.93	D
GERP RS		1.1
PromoterAI		-0.036	Neutral
Varity_R		0.33
gMVP		0.19
Mutation Taster		=17/83	disease causing

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: rs200103892; hg19: chr4-20255564;