12-132639209-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The ENST00000320574.10(POLE):c.5468G>A(p.Arg1823His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,790 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1823C) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000320574.10 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5468G>A | p.Arg1823His | missense_variant | 40/49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5468G>A | p.Arg1823His | missense_variant | 40/48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4547G>A | p.Arg1516His | missense_variant | 32/40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2456G>A | p.Arg819His | missense_variant | 16/24 | XP_011533104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5468G>A | p.Arg1823His | missense_variant | 40/49 | 1 | NM_006231.4 | ENSP00000322570 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152054Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251436Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135902
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461736Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727176
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 06-13-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1823 of the POLE protein (p.Arg1823His). This variant is present in population databases (rs767747669, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405793). 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 POLE 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at