rs758478717
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110H) has been classified as Uncertain significance.
Frequency
Consequence
NM_003995.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPR2 | NM_003995.4 | c.328C>T | p.Arg110Cys | missense_variant | 1/22 | ENST00000342694.7 | |
NPR2 | NM_001378923.1 | c.328C>T | p.Arg110Cys | missense_variant | 1/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPR2 | ENST00000342694.7 | c.328C>T | p.Arg110Cys | missense_variant | 1/22 | 1 | NM_003995.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461848Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 genome ? Cov.: 32
ClinVar
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 | Invitae | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at