Multiple lines of computational evidence (SpliceAI max delta = 0.00) predict no splicing impact for this intronic variant at position +12 of intron 8, satisfying BP4 (supporting benign).1 This intronic variant is outside the conserved splice consensus region, and splicing prediction algorithms uniformly predict no splice alteration, satisfying BP7 (supporting benign).2 This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (GeneDx, VariationID: 386695), satisfying BP6 (supporting benign).3 Three supporting benign criteria (BP4, BP6, BP7) are met. Under generic ACMG/AMP 2015 classification rules, this is sufficient for a Likely benign classification (u22652 supporting benign criteria).4 No pathogenic criteria are met. PVS1 is not met (intronic variant outside canonical splice consensus, no predicted splice effect). PS3 is not met (no functional data). PP3 is not met (SpliceAI predicts no effect). PM2 could not be reliably assessed due to uncertain gnomAD coverage of this intronic position.5
MUTYH
Final classification
Likely Benign
MUTYH c.690+12G>T · p.?
MUTYH
Multiple lines of computational evidence (SpliceAI max delta = 0.00) predict no splicing impact for this intronic variant at position +12 of intron 8, satisfying BP4 (supporting benign).
InSiGHT Hereditary Colorectal Cancer/Polyposis Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting, BP6 supporting, BP7 supporting; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6BP7
Likely Benign
MUTYH c.690+12G>T
BP4 + BP6 + BP7
→
Likely Benign
4
generic_acmg_combination_rules
Gene diagram
· NM_001128425.2 · variants mapped to exon structure
MUTYH
NM_001128425.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 18 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product or splicing. SpliceAI predicts no significant splice alteration (max delta score = 0.00). REVEL and BayesDel could not be assessed for this intronic variant, but the available evidence uniformly indicates a benign computational profile.
SpliceAI max delta = 0.00no predicted donor/acceptor gain or lossPangolin splice scores: SG 0.09
✓
BP6
supporting
Benign
This variant is classified as Likely benign in ClinVar by GeneDx (VariationID: 386695), a clinical diagnostic laboratory. The classification is supported by in silico evidence indicating a conservative change at a poorly conserved position. While a single submitter, GeneDx is a reputable clinical laboratory whose classification constitutes supporting evidence for a benign interpretation.
ClinVar: Likely benignsingle submitter (GeneDxSCV000528440)
✓
BP7
supporting
Benign
NM_001128425.2:c.690+12G>T is an intronic variant at position +12, outside the conserved splice consensus region. SpliceAI predicts no impact on splicing (max delta score = 0.00), with no predicted donor/acceptor gain or loss. This is consistent with a silent intronic change with no predicted functional consequence on splicing.
Intronic variant at +12 positionoutside conserved splice donor consensusSpliceAI max delta = 0.00
Assessed · not applied
Pathogenic
PVS1
NM_001128425.2:c.690+12G>T is an intronic variant at position +12 of intron 8, outside the canonical splice consensus (u00b11,2).
PS2
No de novo observation has been reported for NM_001128425.2:c.690+12G>T in the available evidence.
PS3
No functional studies have been performed on NM_001128425.2:c.690+12G>T.
PS4
No case-control studies or prevalence data comparing affected versus unaffected individuals are available for NM_001128425.2:c.690+12G>T.
PM1
This is an intronic variant at position +12 of intron 8, outside any critical or well-established functional domain.
PM2
gnomAD data for this intronic position could not be reliably assessed.
PM6
No de novo observation has been reported for NM_001128425.2:c.690+12G>T in the available evidence.
PP1
No cosegregation data are available for NM_001128425.2:c.690+12G>T in affected families.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype data are available for this variant.
PP5
ClinVar classifies this variant as Likely benign (single submitter, GeneDx), not as pathogenic.
Benign
BA1
This variant is not observed at an allele frequency >1% in any population database.
BS1
This variant is not observed at an allele frequency >0.3% in any population database.
BS2
No data available for observation of this variant in healthy adult individuals.
BS3
No well-established functional studies have been performed on NM_001128425.2:c.690+12G>T that show no damaging effect.
BS4
No cosegregation data are available to demonstrate lack of segregation with disease for NM_001128425.2:c.690+12G>T.
BP2
BP2 requires observation in trans with a pathogenic variant in a fully penetrant dominant disorder.
BP5
No evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified.
N/A · 7
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
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.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 386695)
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