About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.47C>T, p.(Pro16Leu)
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
PM2Supporting
PM2 · supporting
NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1 population databases, meeting the <0.1% threshold for PM2 in the non-VCEP generic ACMG/AMP framework.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico predictors are concordant for a neutral effect.
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 supporting, BP4 supporting benign; combination = 1 supporting + 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62719848, n = 1 times).
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.
27 criteria with recorded statuses: 2 met · 5 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001904.3:c.47C>T (p.Pro16Leu) is a missense variant in CTNNB1 absent from gnomAD v2.1 and v4.1 population databases (PM2).
Multiple in silico tools (REVEL 0.153, BayesDel -0.111, SpliceAI max delta 0.01) concordantly predict a neutral effect (BP4).
No de novo observations, case-control data, functional studies, segregation data, or ClinVar classifications are available for this variant.
The variant has been reported once in the somatic COSMIC database (COSV62719848) but has no established somatic or germline clinical significance.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868), this variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1 population databases, meeting the <0.1% threshold for PM2 in the non-VCEP generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=0) and gnomAD v4.1 (AF=0).
Sources
BP4 SupportingMultiple lines of computational evidence support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico predictors are concordant for a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.153
- BayesDel -0.111
- SpliceAI max delta 0.01 — all predict benign/neutral.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 p.Pro16 lies in the N-terminal domain (residues 1-138) but is N-terminal to the well-characterized GSK-3beta phosphorylation hotspot at codons 32-45. Cancer Hotspots confirms this residue is not in a statistically significant mutational hotspot, and no critical functional domain has been defined at this exact position. Details ▾Hide ▴
Evidence considered
- Residue 16 is not in a statistically significant hotspot (Cancer Hotspots). It lies outside the GSK-3beta phosphorylation cluster (codons 32-45).
PP3 Multiple in silico tools support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero, benign-leaning), and SpliceAI max delta score 0.01 (no predicted splicing impact). No computational tool predicts a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.153
- BayesDel -0.111
- SpliceAI max delta 0.01 — all predict benign.
Sources
BA1 BA1 requires an allele frequency >1% (non-VCEP threshold). NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 1% threshold. Details ▾Hide ▴
BS1 BS1 requires an allele frequency >0.3% (non-VCEP threshold), greater than expected for the disorder. NM_001904.3:c.47C>T is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 0.3% threshold. Details ▾Hide ▴
BP1 BP1 applies to a missense variant in a gene where primarily truncating variants cause disease. Although most CTNNB1 syndrome-associated variants are truncating (nonsense/frameshift), missense variants are an established disease mechanism in CTNNB1-associated neurodevelopmental disorder. Thus BP1 is not met. Details ▾Hide ▴
Evidence considered
- CTNNB1 missense variants are a documented disease mechanism (PMID:33350591 reports seven new cases with missense variants causing CTNNB1-associated neurodevelopmental disorder).
Sources
3335059141082542
Not assessed · 16 · no assessment recorded
PS1 PS1 requires a different nucleotide change at the same codon with established pathogenicity. No alternate pathogenic variant at codon 16 (e.g., c.47C>G, c.47C>A) is present in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No alternate pathogenic nucleotide change at codon 16 identified.
PS2 PS2 requires a de novo observation with confirmed paternity and maternity. No de novo occurrence of NM_001904.3:c.47C>T has been identified in any public database or literature. Details ▾Hide ▴
Still missing
- No de novo observations of this variant in any database or publication.
PS3 PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No variant-specific functional studies (reporter assays, protein stability, degradation, or MAVE data) were identified for p.Pro16Leu. Details ▾Hide ▴
Still missing
- No functional assay data for p.Pro16Leu.
- No high-throughput functional screen (MAVE) includes this residue.
PS4 PS4 requires significantly increased prevalence of the variant in affected individuals versus controls. This variant is absent from gnomAD (v2.1, v4.1) and has only a single somatic occurrence in COSMIC (COSV62719848). No case-control data are available for statistical comparison. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- single COSMIC somatic entry.
Still missing
- No case-control study or enriched cohort data.
Sources
PM5 PM5 requires a different pathogenic missense change at the same residue (Pro16). No pathogenic missense comparator at codon 16 was identified in ClinVar. The PM5 candidate search returned zero candidates at this residue. Details ▾Hide ▴
Still missing
- No pathogenic missense comparator at Pro16 identified.
Sources
pm5_candidates
PM6 PM6 applies to presumed de novo variants without confirmed paternity/maternity. No de novo observation (presumed or confirmed) of NM_001904.3:c.47C>T exists in the literature or databases. Details ▾Hide ▴
Still missing
- No de novo observations of this variant.
PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data are available for NM_001904.3:c.47C>T. Details ▾Hide ▴
Still missing
- No familial segregation studies for this variant.
PP2 PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. CTNNB1 has both missense and truncating pathogenic variants. HCI prior data are unavailable for this gene, precluding assessment of missense constraint. Cannot be applied without constraint metrics. Details ▾Hide ▴
Still missing
- HCI prior not available for CTNNB1
- missense constraint metrics unavailable.
PP4 PP4 requires a patient phenotype or family history highly specific for the gene. No clinical phenotype data are available for individuals carrying NM_001904.3:c.47C>T. Details ▾Hide ▴
Still missing
- No patient phenotype data available.
PP5 PP5 requires a reputable source to have reported the variant as pathogenic. This variant is absent from ClinVar; no reputable source has classified it. Details ▾Hide ▴
Still missing
- No reputable source has reported this variant.
BS2 BS2 requires observation of the variant in a healthy adult individual, in a gene where full penetrance is expected at an early age. NM_001904.3:c.47C>T has not been observed in any control population. Details ▾Hide ▴
Still missing
- Variant not observed in any healthy control population.
BS3 BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect. No functional studies testing p.Pro16Leu were identified. Details ▾Hide ▴
Still missing
- No functional assay data for p.Pro16Leu demonstrating neutral effect.
BS4 BS4 requires nonsegregation of the variant with disease in affected family members. No segregation data exist for NM_001904.3:c.47C>T. Details ▾Hide ▴
Still missing
- No segregation data available.
BP2 BP2 requires observation in trans with a known pathogenic variant for a recessive disorder, or in cis with a pathogenic variant for a dominant disorder. No phase data are available for NM_001904.3:c.47C>T. Details ▾Hide ▴
Still missing
- No phase data available
- variant not observed in any individual with a second CTNNB1 variant.
BP5 BP5 requires identification of an alternate molecular basis for disease in a case carrying the variant. No such data are available for individuals with NM_001904.3:c.47C>T. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis identified in variant carriers.
BP6 BP6 requires a reputable source to have reported the variant as benign. This variant is absent from ClinVar; no reputable source has classified it. Details ▾Hide ▴
Still missing
- No reputable source has reported this variant.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001904.3:c.47C>T is a missense variant (p.Pro16Leu). PVS1 applies only to null variants (nonsense, frameshift, or canonical +/-1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) classifies this variant as bucket 'other' and does not support application of a generic PVS1 downgrade framework. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 16
- not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions. The variant is a single nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_001904.3:c.47C>T is a missense variant (p.Pro16Leu), not a synonymous change. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 requires both PM5-level evidence (a different pathogenic missense at the same residue) and PS3-level functional data. Neither PM5 nor PS3 evidence is available for this variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.3
- Coding (HGVS c.)
- NM_001904.3:c.47C>T
- Protein (HGVS p.)
- NP_001895.1:p.(Pro16Leu)
- GRCh38
- chr3:41224559 C>T
- GRCh37
- chr3:41266050 C>T
- COSMIC
- COSV62719848
Gene diagram
Every interpreted variant in CTNNB1, mapped onto the exon structure of NM_001904.3. Select a row to find it on the plot.
CTNNB1NM_001904.3
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.153
- BayesDel
- -0.111
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico predictors are concordant for a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.153
- BayesDel -0.111
- SpliceAI max delta 0.01 — all predict benign/neutral.
Sources
PP3 Multiple in silico tools support a benign interpretation: REVEL score 0.153 (well below 0.5 threshold), BayesDel score -0.111 (below zero, benign-leaning), and SpliceAI max delta score 0.01 (no predicted splicing impact). No computational tool predicts a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.153
- BayesDel -0.111
- SpliceAI max delta 0.01 — all predict benign.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_001904.3:c.47C>T is a missense variant (p.Pro16Leu), not a synonymous change. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.153. BayesDel score = -0.111224.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_001904.3%3Ac.47C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41266050-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41224559-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41224559-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.3%3Ac.47C%…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/P16L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=223270324
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.153. BayesDel score = -0.111224.
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 previously been reported in somatic cancers (COSMIC; COSV62719848, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.