19-50407184-C-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_002691.4(POLD1):c.1686+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,592,908 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 Likely benign (★★).
Frequency
Consequence
NM_002691.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.1686+10C>T | intron_variant | Intron 13 of 26 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152158Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000332 AC: 8AN: 241148Hom.: 0 AF XY: 0.0000306 AC XY: 4AN XY: 130740
GnomAD4 exome AF: 0.0000715 AC: 103AN: 1440750Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 48AN XY: 713104
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152158Hom.: 0 Cov.: 30 AF XY: 0.0000673 AC XY: 5AN XY: 74342
ClinVar
Submissions by phenotype
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: POLD1 c.1686+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 241148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1686+10C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
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Carcinoma of colon Benign:1
The POLD1 c.1686+10C>T variant was not identified in the literature. The variant was identified dbSNP (rs372652150) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae and GeneDx). The variant was identified in control databases in 11 of 267,230 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23,800 chromosomes (freq: 0.00008), European in 7 of 123,466 chromosomes (freq: 0.00006), East Asian in 1 of 18,704 chromosomes (freq: 0.00005), and South Asian in 1 of 29,814 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, or Finnish, populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Colorectal cancer, susceptibility to, 10 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at