Genetic Variant SLITRK2:p.Arg274Lys (chrX-145823246-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_032539.5(SLITRK2):c.821G>A(p.Arg274Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,098,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

SLITRK2
NM_032539.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.26

Publications

0 publications found

Variant links:

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

SLITRK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.109986156).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLITRK2	NM_032539.5	MANE Select	c.821G>A	p.Arg274Lys	missense	Exon 5 of 5	NP_115928.1	Q9H156-1
SLITRK2	NM_001144003.3		c.821G>A	p.Arg274Lys	missense	Exon 5 of 5	NP_001137475.1	Q9H156-1
SLITRK2	NM_001144004.3		c.821G>A	p.Arg274Lys	missense	Exon 5 of 5	NP_001137476.1	Q9H156-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLITRK2	ENST00000335565.6	TSL:2 MANE Select	c.821G>A	p.Arg274Lys	missense	Exon 5 of 5	ENSP00000334374.5	Q9H156-1
SLITRK2	ENST00000370490.1	TSL:6	c.821G>A	p.Arg274Lys	missense	Exon 1 of 1	ENSP00000359521.1	Q9H156-1
SLITRK2	ENST00000867861.1		c.821G>A	p.Arg274Lys	missense	Exon 5 of 5	ENSP00000537920.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1098169

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363525

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842072

Other (OTH)

AF:

0.00

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.011

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

3.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.020

REVEL

Benign

0.078

Sift

Benign

0.76

Sift4G

Benign

0.71

Polyphen

0.0

Vest4

0.12

MutPred

0.36

Gain of ubiquitination at R274 (P = 0.0011)

MVP

0.68

MPC

0.55

ClinPred

0.42

GERP RS

4.6

Varity_R

0.25

gMVP

0.44

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over