chr9-35806474-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2PP3_ModeratePP5
The NM_003995.4(NPR2):c.2455C>T(p.Arg819Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003995.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPR2 | NM_003995.4 | c.2455C>T | p.Arg819Cys | missense_variant | 16/22 | ENST00000342694.7 | |
NPR2 | NM_001378923.1 | c.2464C>T | p.Arg822Cys | missense_variant | 16/22 | ||
NPR2 | XM_047423431.1 | c.1060C>T | p.Arg354Cys | missense_variant | 11/17 | ||
NPR2 | XM_024447561.2 | c.1051C>T | p.Arg351Cys | missense_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPR2 | ENST00000342694.7 | c.2455C>T | p.Arg819Cys | missense_variant | 16/22 | 1 | NM_003995.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251446Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727210
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
Short stature with nonspecific skeletal abnormalities Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2013 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2023 | Published functional studies demonstrate a dominant negative effect on cGMP production (PMID: 24001744); Identified in a patient with short stature in published literature (PMID: 24001744); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24001744, 26075495, 33713577) - |
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 | Oct 15, 2020 | Experimental studies have shown that this variant affects NPR2 protein function (PMID: 26075495). 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. This variant has been observed in individual(s) with disproportionate short stature (PMID: 24001744, 26075495). ClinVar contains an entry for this variant (Variation ID: 208356). This variant is present in population databases (rs766256429, ExAC 0.009%). This sequence change replaces arginine with cysteine at codon 819 of the NPR2 protein (p.Arg819Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at