NM_006231.4:c.4952+13C>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).1 SpliceAI predicts no splice impact with a maximum delta score of 0.01, supporting a benign computational interpretation (BP7_Supporting).2 The variant is an intronic substitution at position +13 of intron 37, outside the canonical splice consensus. PVS1 is not applicable; no null variant mechanism is supported.3 The variant is absent from ClinVar with no published literature describing this exact variant. No functional, segregation, case-control, or de novo data are available.4 The León-Castillo et al. 2020 custom POLE framework (local gene-specific framework) covers PM1, PS4, PP3, and BP4 for exonuclease-domain missense variants only. This intronic variant falls outside the framework's scope, and none of the four customized criteria are met under the framework's rules.5 Overall evidence is insufficient for classification. PM2_Supporting and BP7_Supporting provide offsetting weak pathogenic and benign signals. This variant is classified as a Variant of Uncertain Significance (VUS).
POLE
Final classification
VUS
POLE c.4952+13C>A · p.?
POLE
NM_006231.4:c.4952+13C>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
The León-Castillo et al. 2020 custom POLE gene-specific framework was used as primary authority for criterion adjudication; its final combination rules mirror generic ACMG/AMP 2015 (PMID:25741868). The only met criteria are PM2 at supporting strength (absent from gnomAD) and BP7 at supporting benign strength (SpliceAI predicts no splice impact). One pathogenic supporting and one benign supporting criterion offset each other. No combination rule for Pathogenic, Likely Pathogenic, Likely Benign, or Benign is satisfied. The variant falls into the default VUS category.
Classification rationale
PM2
BP7
VUS
POLE c.4952+13C>A
PM2 + BP7
→
VUS
3
pvs1_generic_framework ↗pvs1_variant_assessment
5
vcep_path_250_323vcep_path_250_323_s002vcep_path_250_323_s003vcep_path_250_323_s004
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_006231.4:c.4952+13C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP guidelines, complete absence from large population databases supports PM2 at supporting strength (allele frequency <0.1%).
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
✓
BP7
supporting
Benign
NM_006231.4:c.4952+13C>A is an intronic variant at position +13 of intron 37. SpliceAI predicts no splice impact (max delta score = 0.01, well below the 0.2 threshold for any splice-altering effect). All four delta scores (acceptor gain, acceptor loss, donor gain, donor loss) are ≤0.01. While BP7 was originally defined for synonymous variants, extended ACMG/AMP interpretations support its application to intronic variants at non-conserved positions where splicing algorithms predict no impact on native splicing or creation of a novel splice site.
SpliceAI max delta score 0.01 — no predicted splice alterationAll individual delta scores ≤0.01 (DS_AG=0.01DS_AL=0.0
Assessed · not applied
Pathogenic
PVS1
NM_006231.4:c.4952+13C>A is an intronic substitution at position +13 of intron 37, outside the canonical splice consensus (±1,2).
PS1
No known pathogenic variant has been reported at this exact nucleotide position (c.4952+13).
PS3
No functional data exists for NM_006231.4:c.4952+13C>A.
PS4
The León-Castillo custom POLE framework restricts PS4 to specific exonuclease-domain hotspot missense variants with ≥10 combined COSMIC+TCGA cases.
PM1
The León-Castillo custom POLE framework defines PM1 exclusively for specific exonuclease-domain missense variants.
PM6
No de novo report for NM_006231.4:c.4952+13C>A was identified in any source.
PP1
No segregation data available.
PP3
The León-Castillo custom POLE framework restricts PP3 to exact missense variants appearing in Supplementary Tables S2 or S3 with REVEL class 'likely disease causing' and ≤1 benign in silico result.
PP4
No patient phenotype data is available to assess whether the variant's phenotype is highly specific for a disease.
PP5
NM_006231.4:c.4952+13C>A is absent from ClinVar.
Benign
BA1
NM_006231.4:c.4952+13C>A is absent from all gnomAD databases (allele frequency = 0%).
BS1
NM_006231.4:c.4952+13C>A is absent from all gnomAD databases (allele frequency = 0%).
BS2
No observation of this variant in a homozygous state or in trans with a pathogenic variant in healthy controls.
BS3
No functional studies, either in vivo or in vitro, have been performed for NM_006231.4:c.4952+13C>A demonstrating no damaging effect on protein function or splicing.
BS4
No segregation data available to demonstrate lack of cosegregation with disease in affected family members.
BP2
No data available on whether this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant.
BP4
The León-Castillo custom POLE framework restricts BP4 to exact missense variants in Tables S2/S3 with REVEL 'Likely benign' and ≥4 benign in silico results.
BP5
No observation of this variant in a case with an alternate molecular basis for disease.
BP6
NM_006231.4:c.4952+13C>A is absent from ClinVar.
N/A · 4
PS2 · PM5 · PP2 · BP1
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.01).
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