19-50384391-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_002691.4(POLD1):c.-2+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002691.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.-2+1G>C | splice_donor_variant, intron_variant | Intron 1 of 26 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 0
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:1
This variant is denoted POLD1 c.-2+1G>C or IVS1+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 1 of the POLD1 gene. Of note, exon 1 of POLD1 is a non coding exon, therefore this nucleotide substitution occurs prior to the POLD1 ATG translational start site which is located in exon 2. While this variant destroys the canonical splice donor site in intron 1, possibly leading to exon 1 skipping, it is unknown whether this change will affect the promoter and/or protein translation. POLD1 c.-2+1G>C has been reported in familial pancreatic cancer kindred (Roberts 2016). Based on currently available information, it is unclear whether POLD1 c.-2+1G>C is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.-2+1G>C intronic variant is located in the 5' untranslated region (5’ UTR) of the POLD1 gene. This intronic variant results from a G to C substitution one nucleotide after the first translated codon. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However,loss of function of POLD1 has not been established as a mechanism of disease. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at