9-35792424-C-A

Variant names:

• chr9-35792424-C-A
• NM_003995.4:c.16C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_003995.4(NPR2):​c.16C>A​(p.Leu6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NPR2 NM_003995.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66
• Publications: 0 publications found

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

ENSG00000297929 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25901544).
• BP6: Variant 9-35792424-C-A is Benign according to our data. Variant chr9-35792424-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3772277.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR2	NM_003995.4	c.16C>A	p.Leu6Ile	missense_variant	Exon 1 of 22	ENST00000342694.7	NP_003986.2
NPR2	NM_001378923.1	c.16C>A	p.Leu6Ile	missense_variant	Exon 1 of 22		NP_001365852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPR2	ENST00000342694.7	c.16C>A	p.Leu6Ile	missense_variant	Exon 1 of 22	1	NM_003995.4	ENSP00000341083.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPR2: PM2, PP2, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.0021	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.27
Sift	Benign	0.044	D
Sift4G	Uncertain	0.040	D
Polyphen		0.88	P
Vest4		0.35
MutPred		0.50		Gain of helix (P = 0.0199);
MVP		0.66
MPC		0.76
ClinPred		0.34	T
GERP RS		3.2
PromoterAI		-0.038	Neutral
Varity_R		0.12
gMVP		0.71
Mutation Taster		=97/3	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

hg19: chr9-35792421;