9-35792422-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003995.4(NPR2):c.14C>A(p.Ser5Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NPR2 NM_003995.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.939

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 126 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35792422-C-A is Pathogenic according to our data. Variant chr9-35792422-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 870612.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPR2	NM_003995.4	c.14C>A	p.Ser5Ter	stop_gained	1/22	ENST00000342694.7
NPR2	NM_001378923.1	c.14C>A	p.Ser5Ter	stop_gained	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPR2	ENST00000342694.7	c.14C>A	p.Ser5Ter	stop_gained	1/22	1	NM_003995.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acromesomelic dysplasia 1, Maroteaux type Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Hacettepe Genetic Diseases Diagnosis Center, Hacettepe University Faculty of Medicine

Apr 20, 2020

Sequencing analysis of the NPR2 gene revealed a novel mutation NM_003995.4: c.14C>A (p.Ser5Ter) in a patient presented with disproportionate short stature with short limbs. On physical examination, dolichocephaly, a prominent forehead, depressed nasal root with a bulbous nose, down-slanted palpebral fissures, short limbs, and brachydactyly were noted. Furthermore, radiographic findings of the patient were compatible with Acromesomelic dysplasia, Maroteaux type. This variant was neither reported in ExAC nor gnomAD databases. This variant was classified as pathogenic according to the ACMG Guidelines and predicted to be disease causing by in silico analysis such as MutationTaster. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.19	N
MutationTaster	Benign	1.0	A
Vest4		0.48
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749952755; hg19: chr9-35792419;