19-50407004-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002691.4(POLD1):c.1516C>T(p.Arg506Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,607,328 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. R506H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1516C>T | p.Arg506Cys | missense_variant | 13/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1516C>T | p.Arg506Cys | missense_variant | 13/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000407 AC: 1AN: 245428Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132886
GnomAD4 exome AF: 0.00000619 AC: 9AN: 1455068Hom.: 0 Cov.: 34 AF XY: 0.00000968 AC XY: 7AN XY: 723346
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152260Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1AN XY: 74442
ClinVar
Submissions by phenotype
Colorectal cancer, susceptibility to, 10 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 04, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 506 of the POLD1 protein (p.Arg506Cys). This variant is present in population databases (rs528292347, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 486073). 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 POLD1 protein function with a positive 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. - |
Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2024 | The p.R506C variant (also known as c.1516C>T), located in coding exon 12 of the POLD1 gene, results from a C to T substitution at nucleotide position 1516. The arginine at codon 506 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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