NM_002523.3:c.241C>T

Variant names:

• chr7-98617702-C-T
• rs774900455
• NM_002523.3:c.241C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002523.3(NPTX2):​c.241C>T​(p.Arg81Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,289,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R81G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: NPTX2 NM_002523.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.866
• Publications: 0 publications found

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]

ENSG00000306503 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36021894).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002523.3. 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
	NPTX2	NM_002523.3	MANE Select	c.241C>T	p.Arg81Cys	missense	Exon 1 of 5	NP_002514.1	P47972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPTX2	ENST00000265634.4	TSL:1 MANE Select	c.241C>T	p.Arg81Cys	missense	Exon 1 of 5	ENSP00000265634.3	P47972
	NPTX2	ENST00000903470.1		c.241C>T	p.Arg81Cys	missense	Exon 1 of 5	ENSP00000573529.1
	ENSG00000306503	ENST00000819136.1		n.179+1512G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000233 AC: 3 AN: 1289568 Hom.: 0 Cov.: 31 AF XY: 0.00000158 AC XY: 1 AN XY: 633006

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25378

American (AMR) AF: 0.00 AC: 0 AN: 19530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20248

East Asian (EAS) AF: 0.00 AC: 0 AN: 29102

South Asian (SAS) AF: 0.00 AC: 0 AN: 65436

European-Finnish (FIN) AF: 0.0000318 AC: 1 AN: 31488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3732

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1041168

Other (OTH) AF: 0.00 AC: 0 AN: 53486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.87
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.089
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.24
MutPred		0.30		Loss of MoRF binding (P = 0.0024)
MVP		0.34
MPC		1.0
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.011	Neutral
Varity_R		0.45
gMVP		0.70
Mutation Taster		=79/21	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: rs774900455; hg19: chr7-98247014;