4-20253872-C-G

Variant names:

• chr4-20253872-C-G
• rs769098401
• NM_004787.4:c.57C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004787.4(SLIT2):​c.57C>G​(p.Ile19Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I19I) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SLIT2 NM_004787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08708739).

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.57C>G	p.Ile19Met	missense	Exon 1 of 37	NP_004778.1	O94813-1
	SLIT2	NM_001289135.3		c.57C>G	p.Ile19Met	missense	Exon 1 of 37	NP_001276064.1	O94813-2
	SLIT2	NM_001289136.3		c.57C>G	p.Ile19Met	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.57C>G	p.Ile19Met	missense	Exon 1 of 37	ENSP00000422591.1	O94813-1
	SLIT2	ENST00000503837.5	TSL:1	c.57C>G	p.Ile19Met	missense	Exon 1 of 37	ENSP00000422261.1	O94813-2
	SLIT2	ENST00000503823.5	TSL:1	c.57C>G	p.Ile19Met	missense	Exon 1 of 36	ENSP00000427548.1	O94813-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.23	N
PhyloP100		-0.054
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.19
Sift	Benign	0.052	T
Sift4G	Uncertain	0.048	D
Polyphen		0.019	B
Vest4		0.048
MutPred		0.48		Gain of loop (P = 0.0851)
MVP		0.31
MPC		0.32
ClinPred		0.068	T
GERP RS		1.6
PromoterAI		-0.0042	Neutral
Varity_R		0.054
gMVP		0.12
Mutation Taster		=92/8	polymorphism

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: rs769098401; hg19: chr4-20255495;