BA1 (Stand-alone Benign): the variant is common in general-population databases, with a maximum allele frequency of about 1.5% (African/African American) - far above the 1% threshold and inconsistent with a cause of a severe, predominantly de novo dominant disorder. BS1 (Strong Benign): population allele frequency (up to about 1.5%) far exceeds expectation for CTNNB1 syndrome, and the presence of homozygotes is incompatible with a fully penetrant dominant disease allele. BP7 (Supporting Benign): synonymous (silent) change with no predicted splicing effect (SpliceAI max delta 0.13, below the splice-altering threshold). Overall classification: Benign. Under the ACMG/AMP 2015 rules, the stand-alone BA1 criterion alone is sufficient for Benign; BS1 and BP7 additionally reinforce the call.
CTNNB1
Final classification
Benign
CTNNB1 c.420T>C · p.Ile140=
CTNNB1
BA1 (Stand-alone Benign): the variant is common in general-population databases, with a maximum allele frequency of about 1.5% (African/African American) - far above the 1% threshold and inconsistent with a cause of a severe, predominantly de novo dominant disorder.
No gene-specific classification framework exists for CTNNB1, so the standard ACMG/AMP 2015 rules were applied. BA1 was met at stand-alone benign strength (maximum population allele frequency about 1.5% in African/African American populations, exceeding the 1% threshold), BS1 at strong benign strength (frequency far above expectation for a severe, predominantly de novo dominant disorder, with homozygotes observed), and BP7 at supporting strength (synonymous change with no predicted splicing impact). All pathogenic-direction criteria were either not met or not applicable. Under the ACMG/AMP 2015 combination rules, the single BA1 stand-alone criterion is sufficient for a Benign classification; BS1 and BP7 are consistent with and reinforce this conclusion.
Classification rationale
BA1BS1BP7
Benign
CTNNB1 c.420T>C
BA1 + BS1 + BP7
→
Benign
Gene diagram
· NM_001904.4 · variants mapped to exon structure
CTNNB1
NM_001904.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
Met (stand-alone benign): the variant is a common polymorphism. Its maximum population allele frequency is about 1.5% (African/African American in gnomAD v2.1 and v4.1), far above the 1% threshold expected for a severe, early-onset, predominantly de novo dominant disorder, so it cannot be a common cause of CTNNB1 syndrome.
gnomAD v2.1 record 3-41266623-T-C: overall AF 0.00182667 (516/282,482), AFR AF 0.0157827 (394/24,964, hom 8), grpmax FAF 0.0150438gnomAD v4.1 record 3-41225132-T-C: overall AF 0.000926244 (1,495/1,614,046), AFR AF 0.0149689 (1,123/75,022, hom 15), joint grpmax FAF 0.0142419gnomAD-Canada v1.0 (HostSeq) record 3-41225132-T-C: AF 0.00130293 (24/18,420), AFR AF 0.0147059
✓
BS1
strong
Benign
Met (strong benign): the allele frequency (up to about 1.5% in African/African American populations) far exceeds what is expected for CTNNB1 syndrome, a severe, fully penetrant, predominantly de novo disorder. Observed homozygotes (8 in gnomAD v2.1, 17 in v4.1) are incompatible with a fully penetrant dominant disease allele.
gnomAD v2.1 record 3-41266623-T-C: AFR AF 0.0157827 (394/24,964, hom 8), grpmax FAF 0.0150438gnomAD v4.1 record 3-41225132-T-C: AFR AF 0.0149689 (1,123/75,022, hom 15), joint grpmax FAF 0.0142419gnomAD-Canada v1.0 (HostSeq): AFR AF 0.0147059 (15/1,020)
✓
BP7
supporting
review
Benign
Met (supporting): the variant is synonymous (p.Ile140=) and splice-prediction tools indicate no effect on splicing (SpliceAI max delta 0.13, below the 0.2 threshold), with the change located deep within exon 4, away from splice consensus sites.
Synonymous consequence p.(Ile140=) (Mutalyzer NM_001904.4(NP_001895.1):p.(=); VariantValidator NP_001895.1:p.(Ile140=); gnomAD-Canada VEP 'synonymous_variant')SpliceAI DS_AG 0.13 / DS_AL 0.0 / DS_DG 0.0 / DS_DL 0.0, max delta 0.13 — no splice consensus impact, no new splice site creation above thresholdMutalyzer exon structure: exon 4 spans c.242-c.495; c.420 is ~75 nt from both intron boundaries (outside splice consensus)
Assessed · not applied
Pathogenic
PS2
Not assessed: insufficient evidence was available.
PS3
Not assessed: insufficient evidence was available; no functional assay results could be evaluated for this variant.
PS4
Not met: no case-control or variant-specific case data show enrichment of this variant in affected individuals.
PM2
Not met: the variant is not rare.
PM6
Not assessed: insufficient evidence was available; no parental testing data were available to support an assumed de novo occurrence.
PP1
Not assessed: insufficient evidence was available; no family genotyping or segregation data were reported.
PP3
Not met: no computational evidence indicates a deleterious effect.
PP4
Not assessed: insufficient evidence was available; no phenotype description or family history was available to evaluate whether the variant fits a CTNNB1-related presentation.
PP5
Not met: no expert-panel classification labels this variant pathogenic.
Benign
BS2
Not met: although homozygotes are present in gnomAD, that database does not provide phenotype-verified healthy-adult carrier status, which BS2 requires.
BS3
Not assessed: insufficient evidence was available; no well-established functional studies showing no damaging effect could be evaluated.
BS4
Not assessed: insufficient evidence was available; no family members were genotyped, so lack of segregation could not be demonstrated.
BP2
Not assessed: insufficient evidence was available; no phase (trans/cis) or co-occurrence observations with a pathogenic variant were reported.
BP4
Not met: BP4 requires multiple independent computational lines predicting no impact.
BP5
Not assessed: insufficient evidence was available; no alternate molecular basis of disease (for example, a co-occurring pathogenic variant) was reported for the case.
BP6
Not met: BP6 requires an expert-panel benign classification for this exact variant.
N/A · 9
PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000926244; MAF= 0.09262%, 1495/1614046 alleles, homozygotes = 17) and has highest observed frequency in the African/African American population (AF= 0.0149689; MAF= 1.49689%, 1123/75022 alleles, homozygotes = 15); grpmax FAF= 0.0142419.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00182667; MAF= 0.18267%, 516/282482 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0157827; MAF= 1.57827%, 394/24964 alleles, homozygotes = 8); grpmax FAF= 0.0150438.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0013029315960912053, 24/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.093%
· 1495 / 1,614,046
17 hom · FAF 1.4%
17 hom · FAF 1.4%
African/African American 1123 / 75,022 |
1.5% 15 hom |
Middle Eastern 20 / 6,062 |
0.33% 1 hom |
Ashkenazi Jewish 49 / 29,606 |
0.17% |
Admixed American 98 / 59,974 |
0.16% |
Remaining individuals 78 / 62,502 |
0.12% 1 hom |
European (non-Finnish) 119 / 1,179,986 |
0.01% |
European (Finnish) 5 / 64,020 |
0.0078% |
South Asian 3 / 91,084 |
0.0033% |
+ 2 not observed (Amish, East Asian)
gnomAD v2.1
0.18%
· 516 / 282,482
8 hom · FAF 1.5%
8 hom · FAF 1.5%
African/African American 394 / 24,964 |
1.6% 8 hom |
Ashkenazi Jewish 21 / 10,360 |
0.2% |
Remaining individuals 14 / 7,220 |
0.19% |
Admixed American 52 / 35,352 |
0.15% |
European (non-Finnish) 32 / 128,914 |
0.025% |
European (Finnish) 2 / 25,112 |
0.008% |
South Asian 1 / 30,616 |
0.0033% |
+ 1 not observed (East Asian)
gnomAD Canada 🇨🇦
0.13%
· 24 / 18,420
0 hom · FAF 0.91%
0 hom · FAF 0.91%
African/African American 15 / 1,020 |
1.5% |
Middle Eastern 1 / 144 |
0.69% |
Remaining individuals 4 / 1,138 |
0.35% |
Latino/Admixed American 1 / 838 |
0.12% |
European (non-Finnish) 3 / 11,740 |
0.026% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 709750)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104442201, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & References.
Rule & framework references · cited for criterion definitions, not variant evidence
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR