rs758478717

Positions:

• chr9-35792736-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_003995.4(NPR2):​c.328C>T​(p.Arg110Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPR2 NM_003995.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 4.59

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NPR2. . Gene score misZ 2.9586 (greater than the threshold 3.09). Trascript score misZ 4.5861 (greater than threshold 3.09). GenCC has associacion of gene with short stature with nonspecific skeletal abnormalities, acromesomelic dysplasia 1, Maroteaux type, tall stature-scoliosis-macrodactyly of the great toes syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 9-35792736-C-T is Pathogenic according to our data. Variant chr9-35792736-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208359.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr9-35792736-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPR2	NM_003995.4	c.328C>T	p.Arg110Cys	missense_variant	1/22	ENST00000342694.7	NP_003986.2
NPR2	NM_001378923.1	c.328C>T	p.Arg110Cys	missense_variant	1/22		NP_001365852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPR2	ENST00000342694.7	c.328C>T	p.Arg110Cys	missense_variant	1/22	1	NM_003995.4	ENSP00000341083.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251454 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Short stature with nonspecific skeletal abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2014

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 05, 2020

- -

Acromesomelic dysplasia 1, Maroteaux type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Hacettepe Genetic Diseases Diagnosis Center, Hacettepe University Faculty of Medicine

May 04, 2020

Sequencing analysis of the NPR2 gene revealed two compound heterozygous variants in a patient who presented with disproportionate short stature. Of these two variants, one is a missense variant (c.328C>T, p.Arg110Cys) which has been previously described in the heterozygous state in a patient with short stature. The R110C variant in the NPR2 gene was associated with a significant loss in the C-type natriuretic peptide-dependent cGMP response. This variant has also been shown to have a dominant negative effect and to cause defects in the intracellular trafficking from the endoplasmic reticulum to the Golgi apparatus by in vitro functional studies (Amano et al.,2014). This variant was classified as uncertain significance according to the ACMG guidelines and predicted to be deleterious by in silico pathogenicity prediction tools such as PolyPhen and MutationTaster. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the NPR2 protein (p.Arg110Cys). This variant is present in population databases (rs758478717, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive acromesomelic dysplasia (PMID: 24471569, 33288834). ClinVar contains an entry for this variant (Variation ID: 208359). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPR2 protein function. Experimental studies have shown that this missense change affects NPR2 function (PMID: 24471569). This variant disrupts the p.Arg110 amino acid residue in NPR2. Other variant(s) that disrupt this residue have been observed in individuals with NPR2-related conditions (PMID: 33288834, 35368703), which suggests that this may be a clinically significant amino acid residue. 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.83		Loss of methylation at R110 (P = 0.034);
MVP		0.92
MPC		2.0
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.52
gMVP		0.96

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

Other links and lift over

dbSNP: rs758478717; hg19: chr9-35792733;