chr4-20256718-G-T

Variant names:

• chr4-20256718-G-T
• rs1711888312
• NM_004787.4:c.226G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004787.4(SLIT2):​c.226G>T​(p.Ala76Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000847 in 1,416,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A76P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: SLIT2 NM_004787.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28180826).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.226G>T	p.Ala76Ser	missense	Exon 2 of 37	NP_004778.1	O94813-1
	SLIT2	NM_001289135.3		c.226G>T	p.Ala76Ser	missense	Exon 2 of 37	NP_001276064.1	O94813-2
	SLIT2	NM_001289136.3		c.226G>T	p.Ala76Ser	missense	Exon 2 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.226G>T	p.Ala76Ser	missense	Exon 2 of 37	ENSP00000422591.1	O94813-1
	SLIT2	ENST00000503837.5	TSL:1	c.226G>T	p.Ala76Ser	missense	Exon 2 of 37	ENSP00000422261.1	O94813-2
	SLIT2	ENST00000503823.5	TSL:1	c.226G>T	p.Ala76Ser	missense	Exon 2 of 36	ENSP00000427548.1	O94813-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000847 AC: 12 AN: 1416114 Hom.: 0 Cov.: 23 AF XY: 0.00000850 AC XY: 6 AN XY: 705916

African (AFR) AF: 0.00 AC: 0 AN: 32118

American (AMR) AF: 0.00 AC: 0 AN: 41720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25570

East Asian (EAS) AF: 0.00 AC: 0 AN: 38588

South Asian (SAS) AF: 0.00 AC: 0 AN: 81998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1078508

Other (OTH) AF: 0.0000170 AC: 1 AN: 58756

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.075
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.41	N
PhyloP100		7.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.38	T
Polyphen		0.058	B
Vest4		0.34
MutPred		0.37		Loss of catalytic residue at A76 (P = 0.0224)
MVP		0.75
MPC		1.0
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.17
gMVP		0.27
Mutation Taster		=74/26	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: rs1711888312; hg19: chr4-20258341;