X-145823055-G-T

Variant names:

• chrX-145823055-G-T
• NM_032539.5:c.630G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032539.5(SLITRK2):​c.630G>T​(p.Glu210Asp) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SLITRK2 NM_032539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLITRK2	NM_032539.5	c.630G>T	p.Glu210Asp	missense_variant	Exon 5 of 5	ENST00000335565.6	NP_115928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLITRK2	ENST00000335565.6	c.630G>T	p.Glu210Asp	missense_variant	Exon 5 of 5	2	NM_032539.5	ENSP00000334374.5
SLITRK2	ENST00000370490.1	c.630G>T	p.Glu210Asp	missense_variant	Exon 1 of 1	6		ENSP00000359521.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, X-linked 111 Uncertain:1

Apr 23, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLITRK2 c.630G>T (p.Glu210Asp) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The amino acid at this position is predicted to be located in a beta sheet in the LRR domain (AlphaFold). Computational predictors uncertain as to the impact of this variant on SLITRK2 function. Another variant in the same codon, c.628G>A (p.Glu210Lys), has been reported in a male individual with a neurodevelopmental disorder (El Chehadeh S et al., PMID: 35840571). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.21	T;T
Sift4G	Benign	0.21	T;T
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.69		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.62
MPC		1.4
ClinPred		0.89	D
GERP RS		2.8
Varity_R		0.50
gMVP		0.75

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-144904573;