NM_032539.5:c.221T>C

Variant names:

• chrX-145822646-T-C
• rs2124152159
• NM_032539.5:c.221T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_032539.5(SLITRK2):​c.221T>C​(p.Leu74Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SLITRK2 NM_032539.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 1 publications found

Genes affected

SLITRK2 (HGNC:13449): (SLIT and NTRK like family member 2) This gene encodes an integral membrane protein that contains two N-terminal leucine-rich repeats domains and contains C-terminal regions similar to neurotrophin receptors. The encoded protein may play a role in modulating neurite activity. Alternatively spliced transcript variants encoding the same protein have been described.[provided by RefSeq, Feb 2010]

SLITRK2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked 111

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1956 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked 111.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant X-145822646-T-C is Pathogenic according to our data. Variant chrX-145822646-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1334906.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032539.5. 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
	SLITRK2	NM_032539.5	MANE Select	c.221T>C	p.Leu74Ser	missense	Exon 5 of 5	NP_115928.1	Q9H156-1
	SLITRK2	NM_001144003.3		c.221T>C	p.Leu74Ser	missense	Exon 5 of 5	NP_001137475.1	Q9H156-1
	SLITRK2	NM_001144004.3		c.221T>C	p.Leu74Ser	missense	Exon 5 of 5	NP_001137476.1	Q9H156-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLITRK2	ENST00000335565.6	TSL:2 MANE Select	c.221T>C	p.Leu74Ser	missense	Exon 5 of 5	ENSP00000334374.5	Q9H156-1
	SLITRK2	ENST00000370490.1	TSL:6	c.221T>C	p.Leu74Ser	missense	Exon 1 of 1	ENSP00000359521.1	Q9H156-1
	SLITRK2	ENST00000867861.1		c.221T>C	p.Leu74Ser	missense	Exon 5 of 5	ENSP00000537920.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.78		Loss of stability (P = 0.0791)
MVP		0.76
MPC		1.7
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.92
Mutation Taster		=72/28	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: rs2124152159; hg19: chrX-144904164;