rs1284697545
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_006231.4(POLE):c.6628A>C(p.Lys2210Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K2210K) has been classified as Likely benign.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6628A>C | p.Lys2210Gln | missense_variant | 47/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6628A>C | p.Lys2210Gln | missense_variant | 47/48 | ||
POLE | XM_011534797.4 | c.5707A>C | p.Lys1903Gln | missense_variant | 39/40 | ||
POLE | XM_011534802.4 | c.3616A>C | p.Lys1206Gln | missense_variant | 23/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6628A>C | p.Lys2210Gln | missense_variant | 47/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251128Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135742
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461458Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 727044
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2020 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2210 of the POLE protein (p.Lys2210Gln). This variant is not present in population databases (gnomAD no frequency). 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: 540727). 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. - |
POLE-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | The POLE c.6628A>C variant is predicted to result in the amino acid substitution p.Lys2210Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance by outside laboratories in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/540727/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 02, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at