7-98617867-G-T

Variant names:

• chr7-98617867-G-T
• rs746981096
• NM_002523.3:c.406G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002523.3(NPTX2):​c.406G>T​(p.Asp136Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D136N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPTX2 NM_002523.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.406G>T	p.Asp136Tyr	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.406G>T	p.Asp136Tyr	missense	Exon 1 of 5	ENSP00000265634.3	P47972
	NPTX2	ENST00000903470.1		c.406G>T	p.Asp136Tyr	missense	Exon 1 of 5	ENSP00000573529.1
	ENSG00000306503	ENST00000819136.1		n.179+1347C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404584 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695342

African (AFR) AF: 0.00 AC: 0 AN: 32340

American (AMR) AF: 0.00 AC: 0 AN: 38298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 37552

South Asian (SAS) AF: 0.00 AC: 0 AN: 80996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091714

Other (OTH) AF: 0.00 AC: 0 AN: 58690

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.36		Loss of disorder (P = 0.0324)
MVP		0.36
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.57
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs746981096; hg19: chr7-98247179;