chr9-35792493-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_003995.4(NPR2):​c.85G>A​(p.Val29Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NPR2
NM_003995.4 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.73
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPR2NM_003995.4 linkuse as main transcriptc.85G>A p.Val29Met missense_variant 1/22 ENST00000342694.7
NPR2NM_001378923.1 linkuse as main transcriptc.85G>A p.Val29Met missense_variant 1/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPR2ENST00000342694.7 linkuse as main transcriptc.85G>A p.Val29Met missense_variant 1/221 NM_003995.4 P1P20594-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Acromesomelic dysplasia 1, Maroteaux type;C4014690:Tall stature-scoliosis-macrodactyly of the great toes syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 05, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1428049). This variant has not been reported in the literature in individuals affected with NPR2-related conditions. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 29 of the NPR2 protein (p.Val29Met). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.091
D
MetaRNN
Uncertain
0.50
D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.39
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.014
D
Polyphen
0.93
P
Vest4
0.44
MutPred
0.43
Gain of sheet (P = 0.1451);
MVP
0.74
MPC
1.5
ClinPred
0.91
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.18
gMVP
0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-35792490; API