About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.1648C>T, p.(Arg550Cys)
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the non-VCEP PM2 threshold of 0.1%, supporting rarity in the general population.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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; combination = 1 moderate, 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.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
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.
28 criteria with recorded statuses: 1 met · 6 not met · 15 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The CTNNB1 c.1648C>T (p.Arg550Cys; p.R550C) variant has been reported in ClinVar as a variant of uncertain significance by a single submitter.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting PM2 under the generic ACMG framework.
Available computational evidence is mixed: SpliceAI predicts no significant splice effect with a maximum delta score of 0.05, while REVEL is 0.507 and BayesDel is 0.164625, so the in silico data support neither PP3 nor BP4.
No criteria match.
Met · 1
PM2 ModerateThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the non-VCEP PM2 threshold of 0.1%, supporting rarity in the general population. Details ▾Hide ▴
Not met · 6 · evaluated, threshold not reached
PM1 Available evidence does not show that codon 550 lies in a well-established mutational hotspot or a critical domain without benign variation. Cancer Hotspots did not identify this residue as a statistically significant hotspot, and available curated somatic context did not provide variant-specific hotspot support. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots negative/uncertain for residue R550
- OncoKB provided no variant-specific reviewed evidence
Sources
PM5 No pathogenic or likely pathogenic missense comparator at the same residue was identified in the available evidence, and automated candidate review did not find usable same-residue comparators, so PM5 is not met. Details ▾Hide ▴
Evidence considered
- No same-residue comparator candidates identified
Sources
pm5_candidates
PP3 Computational evidence is mixed and does not consistently support a damaging effect. REVEL was 0.507 and BayesDel was 0.164625, while SpliceAI predicted no significant splice impact with a maximum delta score of 0.05; taken together, these data do not support PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.507
- BayesDel 0.164625
- SpliceAI max delta 0.05
Sources
BA1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is far below the benign BA1 threshold of 1%. Details ▾Hide ▴
BS1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency does not exceed the benign BS1 threshold of 0.3%. Details ▾Hide ▴
BP4 Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, but REVEL was 0.507 and BayesDel was 0.164625, so the available in silico evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.05
- REVEL 0.507
- BayesDel 0.164625
Sources
Not assessed · 15 · no assessment recorded
PS1 No established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 was not assessed. Details ▾Hide ▴
Still missing
- A curated same-amino-acid pathogenic comparator was not identified in the available sources.
PS2 No confirmed de novo occurrence of this variant with a consistent phenotype and documented parental relationships was identified, so PS2 was not assessed. Details ▾Hide ▴
Still missing
- No proband-level de novo report for p.Arg550Cys was identified.
PS3 No well-established functional study of this exact variant was identified showing a damaging effect, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify reviewed variant-specific functional evidence
Still missing
- No variant-specific functional assay for p.Arg550Cys was identified.
Sources
PS4 Available evidence does not show that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed. Details ▾Hide ▴
Evidence considered
- single ClinVar submission
- variant absent from gnomAD v2.1 and v4.1
Still missing
- No affected-vs-control comparison or multiple well-documented affected observations were identified.
Sources
PM6 No assumed de novo occurrence of this variant without full parental confirmation was identified, so PM6 was not assessed. Details ▾Hide ▴
Still missing
- No proband-level inheritance report for p.Arg550Cys was identified.
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Still missing
- No family segregation report for p.Arg550Cys was identified.
PP2 Available evidence does not provide a gene-specific missense-constraint framework for applying PP2 to this variant, so PP2 was not assessed. Details ▾Hide ▴
Still missing
- No supported PP2 framework for CTNNB1 was provided in the available sources.
PP4 No phenotype information for an affected individual carrying this variant was provided, so PP4 was not assessed. Details ▾Hide ▴
Still missing
- No case-specific phenotype data were available.
BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient for BS2, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
Still missing
- No healthy-carrier observations were identified.
Sources
BS3 No well-established functional study of this exact variant was identified showing normal function, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify reviewed variant-specific functional evidence
Still missing
- No benign functional assay for p.Arg550Cys was identified.
Sources
BS4 No family data were identified showing lack of segregation with disease, so BS4 was not assessed. Details ▾Hide ▴
Still missing
- No non-segregation report for p.Arg550Cys was identified.
BP1 Available evidence does not provide a supported gene-level framework for applying BP1 to this missense variant, so BP1 was not assessed. Details ▾Hide ▴
Still missing
- No supported BP1 framework for CTNNB1 was provided in the available sources.
BP2 No evidence was identified that this variant occurs in cis with a pathogenic variant or in trans with a pathogenic variant in a fully explained dominant case, so BP2 was not assessed. Details ▾Hide ▴
Still missing
- No phase data were available.
BP3 No evidence was identified that this variant lies in a repetitive region without known function, so BP3 was not assessed. Details ▾Hide ▴
Still missing
- No repeat-region evidence was available.
BP5 No case-specific phenotype data or alternative molecular diagnosis were provided, so BP5 was not assessed. Details ▾Hide ▴
Still missing
- No alternative cause for disease was identified in an affected individual carrying this variant.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant, NM_001904.4:c.1648C>T (p.Arg550Cys; p.R550C), does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants, so PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- CTNNB1 loss of function is an established germline disease mechanism
- variant-specific PVS1 scaffold classifies this change outside default null-variant buckets
Sources
PM3 N/ANo evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive context, so PM3 is not applicable to the available evidence. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is a missense substitution and does not cause a protein length change from an in-frame insertion, deletion, or stop-loss event, so PM4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PP5 N/AAssertion-only criteria were not applied. ClinVar contains a single submission classifying this variant as uncertain significance, which does not support PP5. Details ▾Hide ▴
BP6 N/AAssertion-only benign criteria were not applied. ClinVar does not contain a benign or likely benign submission for this variant, so BP6 is not applicable. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or intronic change at a position without predicted splice impact, so BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.4
- Coding (HGVS c.)
- NM_001904.4:c.1648C>T
- Protein (HGVS p.)
- NP_001895.1:p.(Arg550Cys)
- GRCh38
- chr3:41234262 C>T
- GRCh37
- chr3:41275753 C>T
- ClinVar
- 1388743
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.507
- BayesDel
- 0.165
How the predictions were used
PP3 Computational evidence is mixed and does not consistently support a damaging effect. REVEL was 0.507 and BayesDel was 0.164625, while SpliceAI predicted no significant splice impact with a maximum delta score of 0.05; taken together, these data do not support PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.507
- BayesDel 0.164625
- SpliceAI max delta 0.05
Sources
BP4 Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, but REVEL was 0.507 and BayesDel was 0.164625, so the available in silico evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.05
- REVEL 0.507
- BayesDel 0.164625
Sources
BP7 N/AThis is a missense variant rather than a synonymous or intronic change at a position without predicted splice impact, so BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.507. BayesDel score = 0.164625.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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 0.050
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/1388743/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41275753-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41234262-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.4%3Ac.1648…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/R550C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CTNNB1+c.1648C%3ET
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1388743)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.507. BayesDel score = 0.164625.
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.