Genetic Variant NPTX2:p.Ser20Arg (chr7-98617521-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002523.3(NPTX2):c.60C>G(p.Ser20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,251,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

NPTX2
NM_002523.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0180

Variant links:

Genes affected

NPTX2 (HGNC:7953): (neuronal pentraxin 2) This gene encodes a member of the family of neuronal petraxins, synaptic proteins that are related to C-reactive protein. This protein is involved in excitatory synapse formation. It also plays a role in clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors at established synapses, resulting in non-apoptotic cell death of dopaminergic nerve cells. Up-regulation of this gene in Parkinson disease (PD) tissues suggests that the protein may be involved in the pathology of PD. [provided by RefSeq, Feb 2009]

NPTX2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053031594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPTX2	NM_002523.3 link	c.60C>G	p.Ser20Arg	missense_variant	Exon 1 of 5	ENST00000265634.4	NP_002514.1	P47972

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPTX2	ENST00000265634.4 link	c.60C>G	p.Ser20Arg	missense_variant	Exon 1 of 5	1	NM_002523.3	ENSP00000265634.3		P47972

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000215

AC:

AN:

46520

Hom.:

AF XY:

0.00

AC XY:

AN XY:

27256

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000160

AC:

AN:

1251138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

612002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000109

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.60C>G (p.S20R) alteration is located in exon 1 (coding exon 1) of the NPTX2 gene. This alteration results from a C to G substitution at nucleotide position 60, causing the serine (S) at amino acid position 20 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.14

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.39

M_CAP

Benign

0.075

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.030

REVEL

Benign

0.042

Sift

Benign

0.76

Sift4G

Benign

0.53

Polyphen

0.0010

Vest4

0.13

MutPred

0.18

Loss of glycosylation at S20 (P = 0.0112);

MVP

0.23

MPC

0.39

ClinPred

0.18

GERP RS

2.3

Varity_R

0.089

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over