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CTNNB1c.452G>AUncertain significance
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Variant interpretation report

CTNNB1 c.452G>A, p.(Arg151His)

NM_001904.4:c.452G>A NP_001895.1:p.(Arg151His) View identifiers
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.

About CTNNB1

No gene-level summary was recorded for this case.

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
PM2Met
PM2

The variant is rare in population databases: gnomAD v4.1 total AF is 0.000117726 (190/1613916) and highest observed population AF is 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 threshold of 0.001 (0.1%). gnomAD v2.1 also shows very low frequency (total AF 0.0000318573; highest population AF 0.000070466).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

generic_acmg

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
190 / 1,613,916 alleles

gnomAD v4.1: 190 / 1,613,916 alleles. Recorded AF 0.000117726. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 8/251120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.0466e-05; MAF= 0.00705%, 8/113530 alleles, homozygotes = 0); grpmax FAF= 3.424e-05.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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
Not assessed

No COSMIC evidence statement is recorded in this case.

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 · 17 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

CTNNB1 NM_001904.4:c.452G>A, p.(Arg151His) is present in gnomAD v4.1 at a total allele frequency of 0.000117726 (190/1613916) with a highest observed population frequency of 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 rarity threshold of 0.001 (0.1%), supporting rarity but not absence from population databases.

SpliceAI predicts a maximum delta score of 0.02, which is below the splice impact threshold of 0.2 and argues against a splice-disrupting effect.

ClinVar contains conflicting single-submitter classifications of likely benign and uncertain significance, so this assertion set does not provide decisive classification evidence.

In the absence of gene-specific criteria, robust case-level enrichment, segregation, de novo, or functional evidence, CTNNB1 p.(Arg151His) is classified as a variant of uncertain significance.

Met · 1

PM2 MetThe variant is rare in population databases: gnomAD v4.1 total AF is 0.000117726 (190/1613916) and highest observed population AF is 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 threshold of 0.001 (0.1%). gnomAD v2.1 also shows very low frequency (total AF 0.0000318573; highest population AF 0.000070466). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF 0.000117726; NFE AF 0.000154237
  • gnomAD v2.1 total AF 0.0000318573; NFE AF 0.000070466
Still missing
  • Population rarity alone does not establish pathogenicity.
Sources
gnomad_v4 ↗gnomad_v2 ↗

Not met · 6 · evaluated, threshold not reached

PS4 No case-control enrichment or multiple affected probands were established, and the PS4 literature screen did not identify supportive case evidence. Details ▾Hide ▴
Evidence considered
  • screen_PS4.json: no supportive PS4 paper passed screening
Still missing
  • Published case-level observations would be needed to reassess PS4.
Sources
PMID:28492532 ↗
PM1 Cancer Hotspots did not identify residue Arg151 as a statistically significant hotspot, so PM1 is not supported by the assembled hotspot evidence. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no hotspot row for CTNNB1 R151
PP3 SpliceAI shows a maximum delta score of 0.02, which is below the commonly used splice concern threshold of 0.2 and does not support splice disruption, and the available REVEL score of 0.466 is not sufficient on its own to establish deleterious computational evidence under a generic ACMG framework. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL 0.466 from prefetch.json
Still missing
  • A calibrated gene-specific missense prediction framework is not available.
Sources
spliceai ↗
BA1 The highest observed gnomAD v4.1 population AF is 0.000154237 (0.01542%), which is below the non-VCEP BA1 threshold of 0.01 (1%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 NFE AF 0.000154237
Sources
gnomad_v4 ↗
BS1 The highest observed gnomAD v4.1 population AF is 0.000154237 (0.01542%), which is below the non-VCEP BS1 threshold of 0.003 (0.3%). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 NFE AF 0.000154237
Sources
gnomad_v4 ↗
BP4 SpliceAI predicts no meaningful splice impact with a max delta score of 0.02, which is below 0.2, but the available generic ACMG evidence set does not provide sufficient calibrated benign missense prediction evidence to apply BP4 because the REVEL score of 0.466 is intermediate and no gene-specific computational framework is available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL 0.466 from prefetch.json
Still missing
  • A calibrated benign computational framework for CTNNB1 missense variants is not available.
Sources
spliceai ↗

Not assessed · 17 · no assessment recorded

PS1 No same-amino-acid pathogenic variant at this residue was documented in the reviewed workspace materials. Details ▾Hide ▴
Still missing
  • Codon-level comparison data were not assembled.
PS2 No de novo occurrence data with confirmed maternity and paternity were provided. Details ▾Hide ▴
Still missing
  • Trio or parental testing data are unavailable.
PS3 No validated functional assay results for CTNNB1 p.(Arg151His) were provided. Details ▾Hide ▴
Still missing
  • Functional study data are unavailable.
PM3 No data on occurrence in trans with a pathogenic variant were provided. Details ▾Hide ▴
Still missing
  • Phase information and additional familial data are unavailable.
PM5 No different pathogenic missense change at codon 151 was documented in the reviewed materials. Details ▾Hide ▴
Still missing
  • Codon-level pathogenic comparison data were not assembled.
PM6 No assumed de novo occurrence without full parental confirmation was provided. Details ▾Hide ▴
Still missing
  • Family-based occurrence data are unavailable.
PP1 No segregation data were provided. Details ▾Hide ▴
Still missing
  • Pedigree and segregation information are unavailable.
PP2 The reviewed workspace did not provide gene-level evidence sufficient to determine whether CTNNB1 has a low rate of benign missense variation and whether missense is a primary established disease mechanism for the relevant germline disorder. Details ▾Hide ▴
Still missing
  • Gene-level missense constraint/mechanism evidence was not assembled.
PP4 No phenotype or family history information specific enough to assess PP4 was provided. Details ▾Hide ▴
Still missing
  • Clinical phenotype details are unavailable.
PP5 PP5 was not applied. ClinVar contains non-expert, conflicting single-submitter interpretations and this criterion is not used as decisive evidence here. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely benign (1 submitter) and Uncertain significance (1 submitter)
Sources
clinvar ↗PMID:28492532 ↗
BS2 No criterion-specific evidence for observation in healthy adults inconsistent with the expected penetrance or age of onset was provided. Details ▾Hide ▴
Evidence considered
  • gnomAD homozygotes = 0
Still missing
  • Clinical context for control observations is unavailable.
BS3 No well-established functional studies demonstrating a benign effect were provided. Details ▾Hide ▴
Still missing
  • Functional benign assay data are unavailable.
BS4 No segregation data demonstrating lack of cosegregation were provided. Details ▾Hide ▴
Still missing
  • Family segregation data are unavailable.
BP1 The reviewed workspace did not provide gene-level disease-mechanism evidence sufficient to support BP1 for CTNNB1 missense variation. Details ▾Hide ▴
Still missing
  • Gene-specific missense versus truncating mechanism data were not assembled.
BP2 No phase information showing the variant in trans with a pathogenic variant or in cis with another variant was provided. Details ▾Hide ▴
Still missing
  • Phase and family data are unavailable.
BP5 No alternate molecular diagnosis or established alternate cause for the phenotype was provided. Details ▾Hide ▴
Still missing
  • Clinical differential diagnosis data are unavailable.
BP6 BP6 was not applied. ClinVar contains conflicting non-expert single-submitter assertions, which do not provide sufficiently strong benign evidence for this review. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely benign (1 submitter) and Uncertain significance (1 submitter)
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense change NM_001904.4:c.452G>A results in p.(Arg151His) rather than a predicted loss-of-function variant, so PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • NM_001904.4:c.452G>A; NP_001895.1:p.(Arg151His)
PM4 N/AThis is a missense substitution and not an in-frame deletion/insertion or stop-loss variant, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • NM_001904.4:c.452G>A
BP3 N/AThis is not an in-frame indel in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • NM_001904.4:c.452G>A
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splice impact; this variant is missense and BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variant p.(Arg151His); SpliceAI max delta score 0.02
Sources
spliceai ↗

Identifiers

Gene
CTNNB1
Transcript
NM_001904.4
Coding (HGVS c.)
NM_001904.4:c.452G>A
Protein (HGVS p.)
NP_001895.1:p.(Arg151His)
GRCh38
chr3:41225164 G>A
GRCh37
chr3:41266655 G>A

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…
gnomAD v4.1 190 / 1,613,916 alleles AF 0.000118 · 0 homozygotes · FAF 0.00014
gnomAD v2.1 8 / 251,120 alleles AF 3.19e-05 · 0 homozygotes · FAF 3.42e-05

By genetic ancestry

gnomAD v4.1

AF 0.00012 · 190 / 1,613,916 alleles · 0 hom · FAF 0.00014
European (non-Finnish)182 / 1,180,000 0.00015
Remaining individuals5 / 62,488 8e-05
African/African American2 / 74,912 2.7e-05
South Asian1 / 91,084 1.1e-05
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Middle Eastern, Ashkenazi Jewish, East Asian, Amish.

gnomAD v2.1

AF 3.2e-05 · 8 / 251,120 alleles · 0 hom · FAF 3.4e-05
European (non-Finnish)8 / 113,530 7e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000117726; MAF= 0.01177%, 190/1613916 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154237; MAF= 0.01542%, 182/1180000 alleles, homozygotes = 0); grpmax FAF= 0.00013971.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 8/251120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.0466e-05; MAF= 0.00705%, 8/113530 alleles, homozygotes = 0); grpmax FAF= 3.424e-05.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI shows a maximum delta score of 0.02, which is below the commonly used splice concern threshold of 0.2 and does not support splice disruption, and the available REVEL score of 0.466 is not sufficient on its own to establish deleterious computational evidence under a generic ACMG framework. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL 0.466 from prefetch.json
Still missing
  • A calibrated gene-specific missense prediction framework is not available.
Sources
spliceai ↗
BP4 SpliceAI predicts no meaningful splice impact with a max delta score of 0.02, which is below 0.2, but the available generic ACMG evidence set does not provide sufficient calibrated benign missense prediction evidence to apply BP4 because the REVEL score of 0.466 is intermediate and no gene-specific computational framework is available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL 0.466 from prefetch.json
Still missing
  • A calibrated benign computational framework for CTNNB1 missense variants is not available.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splice impact; this variant is missense and BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variant p.(Arg151His); SpliceAI max delta score 0.02
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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 v4.1 190 / 1,613,916 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record
Cancer hotspots Captured Cancer Hotspots source record
OncoKB Captured OncoKB source record Open source ↗

All source links

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= 0.000117726; MAF= 0.01177%, 190/1613916 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154237; MAF= 0.01542%, 182/1180000 alleles, homozygotes = 0); grpmax FAF= 0.00013971.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18573e-05; MAF= 0.00319%, 8/251120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.0466e-05; MAF= 0.00705%, 8/113530 alleles, homozygotes = 0); grpmax FAF= 3.424e-05.

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: CTNNB1 (β-catenin), a transcriptional activator, is recurrently mutated in various cancers including endometrial and hepatocellular cancers.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV62702481, n = 2 times).