About CTNNB1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CTNNB1 c.269G>A, p.(Arg90Gln)
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
NM_001904.4:c.269G>A is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada; 1 allele out of 1,613,962 in gnomAD v4.1 (AF = 6.2e-7, 0.000062%), well below the 0.1% PM2 threshold. No homozygotes observed.
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
1 / 1,613,962 alleles
gnomAD v4.1: 1 / 1,613,962 alleles. Recorded AF 6.19593e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV62707932, n = 2 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.
29 criteria with recorded statuses: 1 met · 10 not met · 12 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
NM_001904.4:c.269G>A (p.Arg90Gln) is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada with 1 allele out of 1,613,962 in gnomAD v4.1 (AF 0.000062%), meeting PM2 at moderate strength.
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (VariationID 1378784).
In silico predictors are equivocal (REVEL 0.455, BayesDel 0.221, SpliceAI delta 0.0) and do not meet thresholds for PP3 or BP4.
This variant has been observed in somatic cancers (COSMIC COSV62707932, n = 2); no germline functional evidence is available.
No de novo, segregation, case-control, or functional data are available for this variant. Multiple criteria remain unassessed.
No criteria match.
Met · 1
PM2 ModerateNM_001904.4:c.269G>A is at extremely low frequency in population databases: absent from gnomAD v2.1 and gnomAD-Canada; 1 allele out of 1,613,962 in gnomAD v4.1 (AF = 6.2e-7, 0.000062%), well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 1/1
- 613
- 962 alleles (AF 6.2e-7)
- highest in NFE (1/1
- 179
- 938
- AF 8.5e-7)
- 0 homozygotes.
- gnomAD-Canada: absent.
Sources
Not met · 10 · evaluated, threshold not reached
PS3 No well-established in vitro or in vivo functional studies demonstrate a damaging effect of NM_001904.4:c.269G>A (p.Arg90Gln). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No published functional data were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence curated.
Still missing
- No published functional studies of p.Arg90Gln in CTNNB1.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot. Residue Arg90 is not identified as a recurrently mutated position in CTNNB1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue_significant=false
- exact_variant_listed=no.
PP3 In silico predictors do not reach damaging thresholds: REVEL score 0.455 is below the 0.5 threshold, BayesDel score 0.221 is below the 0.27 threshold, and SpliceAI predicts no splice impact (max delta = 0.0). No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.455 (< 0.5 damaging threshold).
- BayesDel: 0.220613 (< 0.27 damaging threshold).
- SpliceAI: max delta = 0.0 (no predicted splice impact).
Sources
PP5 No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Labcorp/Invitae) classifies it as Uncertain significance. Details ▾Hide ▴
BA1 Allele frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below the 1% BA1 threshold. Details ▾Hide ▴
BS1 Allele frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below the 0.3% BS1 threshold. Details ▾Hide ▴
BP1 BP1 applies when primarily truncating variants cause disease in a gene. In CTNNB1, missense variants are a well-established disease mechanism — both missense and truncating variants cause CTNNB1 syndrome (PMIDs 33350591, 36083290). Details ▾Hide ▴
Evidence considered
- PMID 33350591: Missense variants in CTNNB1 associated with neurodevelopmental disorder and vitreoretinopathy.
- PMID 36083290: 404 individuals with CTNNB1 neurodevelopmental disorders include missense variants.
BP4 Multiple lines of computational evidence do not consistently suggest no impact on the gene product. SpliceAI predicts no splice effect (delta = 0.0), but REVEL is borderline (0.455, just below 0.5) and BayesDel (0.221) does not clearly support benign impact. The evidence is equivocal. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.0.
- REVEL: 0.455 (borderline).
- BayesDel: 0.221 (below 0.27 damaging threshold but not strongly benign).
Sources
BP6 No reputable source has classified this variant as benign. ClinVar reports Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 1378784: Uncertain significance (not benign).
Sources
PS5 No reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance from a single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (criteria provided
- single submitter).
Sources
Not assessed · 12 · no assessment recorded
PS1 No established pathogenic missense variant at the same amino acid residue (Arg90) is available for comparison. Same-residue comparator search returned no candidates. Details ▾Hide ▴
Still missing
- No ClinVar pathogenic/likely pathogenic missense variants at residue Arg90 of CTNNB1.
PS2 No de novo observation with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴
Still missing
- No de novo data in ClinVar submissions or published literature.
PS4 Prevalence in affected individuals versus controls has not been established. A single ClinVar submission (Labcorp/Invitae, VUS) is insufficient for case-control assessment. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 1378784: single clinical laboratory submission classified as Uncertain significance.
Still missing
- No case-control or cohort data comparing variant frequency in CTNNB1-affected versus control populations.
Sources
PM6 No de novo observation (without confirmation of maternity/paternity) is available for this variant. Details ▾Hide ▴
Still missing
- No de novo data in ClinVar submissions or published literature.
PP1 No co-segregation data with disease in multiple affected family members is available. Details ▾Hide ▴
Still missing
- No family segregation studies available for this variant.
PP2 Insufficient data to assess whether CTNNB1 has a low rate of benign missense variation (e.g., gnomAD missense Z-score or constraint metric not available in this case). While missense variants in CTNNB1 are a known disease mechanism in CTNNB1 syndrome, formal constraint metrics are absent. Details ▾Hide ▴
Still missing
- No gnomAD missense constraint metric (Z-score
- o/e) available for CTNNB1 in this case.
PP4 No patient phenotype or family history data are available to assess phenotypic specificity for CTNNB1 syndrome. Details ▾Hide ▴
Still missing
- No proband phenotype data available.
BS2 No data available regarding observation of this variant in healthy adults where full penetrance of CTNNB1 syndrome would be expected at an early age. Details ▾Hide ▴
Still missing
- No data on observation in healthy adult controls with confirmed phenotype.
BS3 No well-established functional studies demonstrate no damaging effect of this variant. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
BS4 No non-segregation data with disease phenotype in multiple affected family members is available. Details ▾Hide ▴
Still missing
- No family segregation data.
BP2 No data available regarding observation in trans with a known pathogenic CTNNB1 variant. Details ▾Hide ▴
Still missing
- No trans-configuration data.
BP5 No data available regarding a case with an alternative molecular cause for disease. Details ▾Hide ▴
Still missing
- No alternate molecular cause data.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies to null variants (nonsense, frameshift, canonical splice). NM_001904.4:c.269G>A is a missense variant (p.Arg90Gln) and does not fall into any null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders. CTNNB1 syndrome is an autosomal dominant disorder. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length-altering variants (in-frame indels, stop-loss). This variant is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo established pathogenic missense variant at the same amino acid residue (Arg90) has been identified. PM5 candidate harvesting returned zero comparators. Details ▾Hide ▴
Evidence considered
- pm5_candidates: found=false
- same_residue_candidates=0.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions or insertions in non-repeat regions. This variant is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001904.4:c.269G>A is a missense variant (p.Arg90Gln), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense substitution (c.269G>A
- p.Arg90Gln) — not synonymous.
Identifiers
- Gene
- CTNNB1
- Transcript
- NM_001904.4
- Coding (HGVS c.)
- NM_001904.4:c.269G>A
- Protein (HGVS p.)
- NP_001895.1:p.(Arg90Gln)
- GRCh38
- chr3:41224981 G>A
- GRCh37
- chr3:41266472 G>A
- ClinVar
- 1378784
- COSMIC
- COSV62707932
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 / 1,613,962 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 / 1,613,962 alleles · 0 hom
| European (non-Finnish)1 / 1,179,938 | 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.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19593e-07; MAF= 0.00006%, 1/1613962 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47502e-07; MAF= 0.00008%, 1/1179938 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.455
- BayesDel
- 0.221
How the predictions were used
PP3 In silico predictors do not reach damaging thresholds: REVEL score 0.455 is below the 0.5 threshold, BayesDel score 0.221 is below the 0.27 threshold, and SpliceAI predicts no splice impact (max delta = 0.0). No multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.455 (< 0.5 damaging threshold).
- BayesDel: 0.220613 (< 0.27 damaging threshold).
- SpliceAI: max delta = 0.0 (no predicted splice impact).
Sources
BP4 Multiple lines of computational evidence do not consistently suggest no impact on the gene product. SpliceAI predicts no splice effect (delta = 0.0), but REVEL is borderline (0.455, just below 0.5) and BayesDel (0.221) does not clearly support benign impact. The evidence is equivocal. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.0.
- REVEL: 0.455 (borderline).
- BayesDel: 0.221 (below 0.27 damaging threshold but not strongly benign).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001904.4:c.269G>A is a missense variant (p.Arg90Gln), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense substitution (c.269G>A
- p.Arg90Gln) — not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = 0.220613.
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 / 1,613,962 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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/1378784/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-41266472-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-41224981-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-41224981-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001904.4%3Ac.269G…
- OncoKB ↗www.oncokb.org/gene/CTNNB1/R90Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=223262504
- 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= 6.19593e-07; MAF= 0.00006%, 1/1613962 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47502e-07; MAF= 0.00008%, 1/1179938 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1378784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = 0.220613.
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; COSV62707932, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.