About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.362A>C, p.(Asn121Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is present at extremely low frequency in population databases, well below the 0.1% threshold: absent from gnomAD v2.1 and present in only 1/1,614,112 alleles in gnomAD v4.1 (AF=6.2e-07, 0.000062%). gnomAD Canada reports 2/18,420 alleles (AF=0.01%, highest subpopulation NFE AF=0.017%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest this variant does not impact protein function: REVEL score 0.176 (below disease-causing threshold of 0.5), BayesDel score -0.206 (negative, favors benign), and SpliceAI max delta 0.19 (no predicted splicing impact).
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,614,112 alleles
gnomAD v4.1: 1 / 1,614,112 alleles. Recorded AF 6.19536e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).
SpliceAI score
0.190 maximum delta
Recorded SpliceAI maximum delta score: 0.190. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2 is met at moderate strength: this variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,614,112 alleles, AF=6.2e-07) and gnomAD Canada (2/18,420 alleles, AF=0.01%), all well below the 0.1% population frequency threshold.
BP4 is met at supporting benign strength: multiple in silico predictors (REVEL 0.176, BayesDel -0.206, SpliceAI max delta 0.19) do not predict a damaging effect on protein function or splicing.
All pathogenic criteria other than PM2 are not met: PS3 (no functional data), PP3 (in silico predictors favor benign, not pathogenic), PM1 (not in a hotspot or critical functional residue), PM5 (no pathogenic comparators at same residue), PS1/PS5 (no alternative nucleotide changes at same codon), PP5 (ClinVar VUS, not 3-star pathogenic).
All benign criteria other than BP4 are not met: BA1/BS1 (population frequency too low), BP1 (missense is a known disease mechanism in CTNNB1), BP6 (ClinVar is VUS, not benign).
With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the overall classification is Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules. The moderate evidence for rarity is partially offset by computational evidence suggesting no functional impact.
No criteria match.
Met · 2
PM2 ModerateThis variant is present at extremely low frequency in population databases, well below the 0.1% threshold: absent from gnomAD v2.1 and present in only 1/1,614,112 alleles in gnomAD v4.1 (AF=6.2e-07, 0.000062%). gnomAD Canada reports 2/18,420 alleles (AF=0.01%, highest subpopulation NFE AF=0.017%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 1/1
- 614
- 112 alleles (AF=6.2e-07)
- highest NFE AF=8.5e-07
- gnomAD Canada: 2/18
- 420 alleles (AF=0.01%)
- highest NFE AF=0.017%
- ClinVar submitter also applied PM2
Sources
BP4 SupportingMultiple lines of computational evidence suggest this variant does not impact protein function: REVEL score 0.176 (below disease-causing threshold of 0.5), BayesDel score -0.206 (negative, favors benign), and SpliceAI max delta 0.19 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.176 (benign range)
- BayesDel: -0.206 (benign range)
- SpliceAI: max delta 0.19 (no predicted splicing alteration)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No evidence that a different nucleotide substitution at codon 121 producing the same amino acid change (p.Asn121Thr) has been reported as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at codon 121 reported as pathogenic in ClinVar
- PM5 candidate search found no same-residue comparator variants
Still missing
- No systematic search for alternative nucleotide changes producing N121T across other databases
Sources
clinvar ↗pm5_candidates
PS2 No de novo data available for this variant; both maternity and paternity confirmation would be required. Details ▾Hide ▴
Still missing
- No parental testing data available
PS3 No variant-specific functional data identified. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. No publications with experimental characterization of N121T were identified in the available literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- not reviewed
- no variant-specific functional evidence
Still missing
- No functional studies of N121T identified
- CTNNB1 syndrome functional studies exist (PMID:41082542) but do not mention this specific variant
Sources
PS4 No case-control or prevalence data comparing affected individuals to controls available for this variant. Details ▾Hide ▴
Still missing
- No case-control studies identified
PM1 Residue 121 is not in a statistically significant mutational hotspot (cancerhotspots.org negative). While the N-terminal domain (aa 1-150) of β-catenin contains the GSK3β-mediated degradation signal, residue N121 is not one of the critical phosphorylation sites (S33, S37, T41, S45) and no literature specifically identifies N121 as a functionally critical residue within this domain. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: no hotspot at residue 121
- N121 is in the N-terminal domain but not at a known critical functional residue (key phosphorylation sites are S33
- S37
- T41
- S45)
Still missing
- No domain-specific functional characterization of residue N121 identified
Sources
PM5 No pathogenic missense variants at the same amino acid residue (codon 121) were identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 candidates at codon 121
- ClinVar: no other missense at residue 121 classified as pathogenic
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation reported for this variant. Confirmation of maternity and paternity would be required to apply this criterion. Details ▾Hide ▴
Still missing
- No de novo testing data
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data
PP2 Although CTNNB1 missense variants are a known mechanism of neurodevelopmental disease (CTNNB1 syndrome), no specific missense constraint metric (e.g., Z-score) was available to establish a low rate of benign missense variation in this gene. Details ▾Hide ▴
Evidence considered
- CTNNB1 missense variants associated with neurodevelopmental disorder per PMID:33350591 and PMID:36083290
- No missense Z-score or constraint data available
Still missing
- Missense constraint metrics (Z-score
- gnomAD constraint) not available
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold, favors benign), BayesDel score -0.206 (negative, favors benign), SpliceAI max delta 0.19 (below 0.2 threshold, no splicing impact predicted). Details ▾Hide ▴
Evidence considered
- REVEL: 0.176 (benign-leaning)
- BayesDel: -0.206 (benign)
- SpliceAI max delta: 0.19 (no splice impact)
- HCI Prior: gene not supported
Sources
PP4 No patient-specific phenotype or clinical data available for assessment. Details ▾Hide ▴
Still missing
- No proband phenotype data provided
PP5 ClinVar classification is Uncertain significance from a single clinical laboratory (Labcorp/Invitae), with review status 'criteria provided, single submitter' (1 star). PP5 requires a 3-star expert panel classification as pathogenic to apply at supporting strength. The single-submitter VUS classification does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar VCV001398665: Uncertain significance
- 1 star
- 1 submitter
- Not a 3-star expert panel classification
Sources
BA1 The highest observed allele frequency is 0.017% (gnomAD Canada, NFE population), which is well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Maximum AF: 0.017% in gnomAD Canada NFE
- All populations well below 1% BA1 threshold
Sources
BS1 The highest observed allele frequency is 0.017% (gnomAD Canada, NFE population), which is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Maximum AF: 0.017% in gnomAD Canada NFE
- All populations below 0.3% BS1 threshold
Sources
BS2 No data available regarding observation of this variant in healthy adult individuals to assess for full-penetrance expectation mismatch. Details ▾Hide ▴
Still missing
- No healthy adult carrier data
BS3 No functional studies demonstrating a neutral or benign effect for this variant have been identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional data reviewed
Still missing
- No functional studies of N121T
Sources
BS4 No segregation data available to assess lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data
BP1 CTNNB1 missense variants are a known disease mechanism for CTNNB1-associated neurodevelopmental disorder (PMID:33350591). The gene does not exhibit a disease mechanism restricted exclusively to truncating variants. Details ▾Hide ▴
Evidence considered
- PMID:33350591: Missense variants in CTNNB1 cause vitreoretinopathy and neurodevelopmental disorder
BP2 No data available on observation of this variant in trans with a pathogenic variant. Details ▾Hide ▴
Still missing
- No trans-phase data
BP5 No data available indicating this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data
BP6 ClinVar classification is Uncertain significance (1 star, single submitter), not benign. BP6 requires a 3-star expert panel classification as benign to apply at supporting strength. Details ▾Hide ▴
PS5 No alternative nucleotide change at codon 121 producing the same p.Asn121Thr amino acid substitution has been reported as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide substitution at codon 121 identified in ClinVar
Still missing
- No systematic search across all databases for alternate nucleotide changes at codon 121
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (p.Asn121Thr) does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant bucket: other (missense)
- apply_generic_pvs1_framework: false
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans; CTNNB1-associated disease is autosomal dominant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss); this is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (p.Asn121Thr), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.4
- Coding (HGVS c.)
- NM_001904.4:c.362A>C
- Protein (HGVS p.)
- NP_001895.1:p.(Asn121Thr)
- GRCh38
- chr3:41225074 A>C
- GRCh37
- chr3:41266565 A>C
- ClinVar
- 1398665
Gene diagram
Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001904.4. Select a row to find it on the plot.
CTNNB1NM_001904.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CTNNB1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,614,112 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,112 alleles · 0 hom
| European (non-Finnish)1 / 1,179,996 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19536e-07; MAF= 0.00006%, 1/1614112 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4746e-07; MAF= 0.00008%, 1/1179996 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.176
- BayesDel
- -0.206
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest this variant does not impact protein function: REVEL score 0.176 (below disease-causing threshold of 0.5), BayesDel score -0.206 (negative, favors benign), and SpliceAI max delta 0.19 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.176 (benign range)
- BayesDel: -0.206 (benign range)
- SpliceAI: max delta 0.19 (no predicted splicing alteration)
Sources
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.176 (below 0.5 threshold, favors benign), BayesDel score -0.206 (negative, favors benign), SpliceAI max delta 0.19 (below 0.2 threshold, no splicing impact predicted). Details ▾Hide ▴
Evidence considered
- REVEL: 0.176 (benign-leaning)
- BayesDel: -0.206 (benign)
- SpliceAI max delta: 0.19 (no splice impact)
- HCI Prior: gene not supported
Sources
BP7 N/AThis is a missense variant (p.Asn121Thr), not a synonymous variant with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.176. BayesDel score = -0.205682.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,112 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.190
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1398665/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41266565-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41225074-A-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41225074-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.4%3Ac.362A…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/N121T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CTNNB1+c.362A%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19536e-07; MAF= 0.00006%, 1/1614112 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4746e-07; MAF= 0.00008%, 1/1179996 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1398665)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.176. BayesDel score = -0.205682.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.