rs370333081
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_024529.5(CDC73):c.806C>G(p.Pro269Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P269S) has been classified as Uncertain significance.
Frequency
Consequence
NM_024529.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDC73 | NM_024529.5 | c.806C>G | p.Pro269Arg | missense_variant | 8/17 | ENST00000367435.5 | |
CDC73 | XM_006711537.5 | c.806C>G | p.Pro269Arg | missense_variant | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDC73 | ENST00000367435.5 | c.806C>G | p.Pro269Arg | missense_variant | 8/17 | 1 | NM_024529.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251256Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135810
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460420Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726698
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Parathyroid carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 269 of the CDC73 protein (p.Pro269Arg). This variant is present in population databases (rs370333081, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CDC73-related conditions. ClinVar contains an entry for this variant (Variation ID: 462769). 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 not expected to disrupt CDC73 protein function with a negative predictive value of 80%. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Located in the critical domain interacting with Set1-like complex (Rbbp5 and Ash2L) and binding to hPaf1 complex (Rozenblatt-Rosen et al., 2005); This variant is associated with the following publications: (PMID: 15632063) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2022 | The p.P269R variant (also known as c.806C>G), located in coding exon 8 of the CDC73 gene, results from a C to G substitution at nucleotide position 806. The proline at codon 269 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at