NM_002691.4:c.2718-24A>C is an intronic variant in POLD1 located 24 bases upstream of exon 21, outside the canonical splice consensus region. SpliceAI predicts no significant splicing impact (max delta score = 0.00), indicating this variant is unlikely to alter normal splicing (BP4).1 The variant is present in gnomAD v2.1 at an allele frequency of 0.458% (358/78,106 alleles) and in v4.1 at 0.494% (2,810/568,564 alleles), far exceeding the maximum credible population frequency for a highly penetrant rare dominant disorder such as polymerase proofreading-associated polyposis (BS1).2 The variant is absent from ClinVar with no disease associations or submissions, and no publications were identified that specifically mention this variant.3 Based on the generic ACMG/AMP 2015 classification framework (PMID:25741868), the combination of one strong benign criterion (BS1) and one supporting benign criterion (BP4) supports a classification of Likely Benign.4
POLD1
Final classification
Likely Benign
POLD1 c.2718-24A>C · p.?
POLD1
NM_002691.4:c.2718-24A>C is an intronic variant in POLD1 located 24 bases upstream of exon 21, outside the canonical splice consensus region.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong benign, BP4 supporting benign; combination = 1 strong benign + 1 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP4
Likely Benign
POLD1 c.2718-24A>C
BS1 + BP4
→
Likely Benign
Gene diagram
· NM_002691.4 · variants mapped to exon structure
POLD1
NM_002691.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00494228; MAF= 0.49423%, 2810/568564 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.189655; MAF= 18.96552%, 11/58 alleles, homozygotes = 0); grpmax FAF= 0.0204173.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00458351; MAF= 0.45835%, 358/78106 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.0155039; MAF= 1.55039%, 96/6192 alleles, homozygotes = 0); grpmax FAF= 0.0653219.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.49%
· 2810 / 568,564
0 hom · FAF 2%
0 hom · FAF 2%
Amish 11 / 58 |
19% |
African/African American 509 / 23,140 |
2.2% |
European (Finnish) 158 / 14,032 |
1.1% |
Admixed American 164 / 24,242 |
0.68% |
Ashkenazi Jewish 64 / 11,834 |
0.54% |
South Asian 195 / 45,812 |
0.43% |
European (non-Finnish) 1598 / 412,362 |
0.39% |
Remaining individuals 80 / 22,614 |
0.35% |
Middle Eastern 5 / 1,790 |
0.28% |
East Asian 26 / 12,680 |
0.21% |
gnomAD v2.1
0.46%
· 358 / 78,106
0 hom · FAF 6.5%
0 hom · FAF 6.5%
European (Finnish) 96 / 6,192 |
1.6% |
Admixed American 83 / 9,532 |
0.87% |
Remaining individuals 12 / 2,268 |
0.53% |
South Asian 57 / 12,620 |
0.45% |
African/African American 20 / 5,134 |
0.39% |
European (non-Finnish) 78 / 32,444 |
0.24% |
Ashkenazi Jewish 10 / 4,938 |
0.2% |
East Asian 2 / 4,978 |
0.04% |
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links