19-50403595-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002691.4(POLD1):āc.1240A>Gā(p.Lys414Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,445,296 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K414R) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense, splice_region
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 |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1240A>G | p.Lys414Glu | missense_variant, splice_region_variant | 10/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.1240A>G | p.Lys414Glu | missense_variant, splice_region_variant | 10/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445296Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 720032
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 09, 2017 | The p.Lys414Glu variant in POLD1 has not been previously reported in individuals with colorectal cancer or in large population studies. This variant is located in the last three bases of the exon, which is part of the 5? splice region. Spli cing prediction tools do not suggest an impact to splicing and computational too ls and conservation analysis do not provide strong support for or against an imp act to the protein. However, this information is not predictive enough to rule o ut pathogenicity. In summary, the clinical significance of the p.Lys414Glu varia nt is uncertain. - |
Colorectal cancer, susceptibility to, 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 02, 2021 | This variant has not been reported in the literature in individuals affected with POLD1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 505589). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 414 of the POLD1 protein (p.Lys414Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at