NM_003995.4:c.2455C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP2PP3_ModeratePP5

The NM_003995.4(NPR2):c.2455C>T(p.Arg819Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

NPR2
NM_003995.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.40

Publications

3 publications found

Variant links:

Genes affected

NPR2 (HGNC:7944): (natriuretic peptide receptor 2) This gene encodes natriuretic peptide receptor B, one of two integral membrane receptors for natriuretic peptides. Both NPR1 and NPR2 contain five functional domains: an extracellular ligand-binding domain, a single membrane-spanning region, and intracellularly a protein kinase homology domain, a helical hinge region involved in oligomerization, and a carboxyl-terminal guanylyl cyclase catalytic domain. The protein is the primary receptor for C-type natriuretic peptide (CNP), which upon ligand binding exhibits greatly increased guanylyl cyclase activity. Mutations in this gene are the cause of acromesomelic dysplasia Maroteaux type. [provided by RefSeq, Jul 2008]

NPR2 Gene-Disease associations (from GenCC):

acromesomelic dysplasia 1, Maroteaux type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
short stature with nonspecific skeletal abnormalities 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
tall stature-scoliosis-macrodactyly of the great toes syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

NPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP2

Missense variant in the NPR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 2.9586 (below the threshold of 3.09). Trascript score misZ: 4.5861 (above the threshold of 3.09). GenCC associations: The gene is linked to tall stature-scoliosis-macrodactyly of the great toes syndrome, acromesomelic dysplasia 1, Maroteaux type, short stature with nonspecific skeletal abnormalities 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 9-35806474-C-T is Pathogenic according to our data. Variant chr9-35806474-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208356.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003995.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPR2	NM_003995.4	MANE Select	c.2455C>T	p.Arg819Cys	missense	Exon 16 of 22	NP_003986.2
	NPR2	NM_001378923.1		c.2464C>T	p.Arg822Cys	missense	Exon 16 of 22	NP_001365852.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPR2	ENST00000342694.7	TSL:1 MANE Select	c.2455C>T	p.Arg819Cys	missense	Exon 16 of 22	ENSP00000341083.2
NPR2	ENST00000687787.1		c.2614C>T	p.Arg872Cys	missense	Exon 15 of 21	ENSP00000509440.1
NPR2	ENST00000693094.1		c.2455C>T	p.Arg819Cys	missense	Exon 16 of 22	ENSP00000510161.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251446

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111942

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Short stature with nonspecific skeletal abnormalities

Pathogenic:1

Oct 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Acromesomelic dysplasia 1, Maroteaux type

Pathogenic:1

Dec 19, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 24001744). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.72 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NPR2 related disorder (ClinVar ID: VCV000208356 /PMID: 24001744). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

not provided

Pathogenic:1

Dec 08, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a dominant negative effect on cGMP production (PMID: 24001744); Identified in a patient with short stature in published literature (PMID: 24001744); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24001744, 26075495, 33713577)

Acromesomelic dysplasia 1, Maroteaux type;C4014690:Tall stature-scoliosis-macrodactyly of the great toes syndrome

Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 819 of the NPR2 protein (p.Arg819Cys). This variant is present in population databases (rs766256429, gnomAD 0.006%). This missense change has been observed in individual(s) with disproportionate short stature (PMID: 24001744, 26075495, 33713577). ClinVar contains an entry for this variant (Variation ID: 208356). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPR2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPR2 function (PMID: 26075495). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.9

PhyloP100

1.4

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.72

MVP

0.97

MPC

2.0

ClinPred

1.0

GERP RS

4.2

Varity_R

0.71

gMVP

0.82

Mutation Taster

=15/85

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over