NM_032539.5:c.74C>A

Variant names:

• chrX-145822499-C-A
• rs2073039955
• NM_032539.5:c.74C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_032539.5(SLITRK2):​c.74C>A​(p.Ala25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,501 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. 14/21 in silico tools predict 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. A25V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: SLITRK2 NM_032539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 0 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: 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=0.212232).

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.74C>A	p.Ala25Asp	missense	Exon 5 of 5	NP_115928.1	Q9H156-1
	SLITRK2	NM_001144003.3		c.74C>A	p.Ala25Asp	missense	Exon 5 of 5	NP_001137475.1	Q9H156-1
	SLITRK2	NM_001144004.3		c.74C>A	p.Ala25Asp	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.74C>A	p.Ala25Asp	missense	Exon 5 of 5	ENSP00000334374.5	Q9H156-1
	SLITRK2	ENST00000370490.1	TSL:6	c.74C>A	p.Ala25Asp	missense	Exon 1 of 1	ENSP00000359521.1	Q9H156-1
	SLITRK2	ENST00000867861.1		c.74C>A	p.Ala25Asp	missense	Exon 5 of 5	ENSP00000537920.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097501 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362873

African (AFR) AF: 0.0000379 AC: 1 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841474

Other (OTH) AF: 0.00 AC: 0 AN: 46071

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.17
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.070	B
Vest4		0.50
MVP		0.81
MPC		0.86
ClinPred		0.64	D
GERP RS		3.8
Varity_R		0.37
gMVP		0.73
Mutation Taster		=76/24	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: rs2073039955; hg19: chrX-144904017;