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CTNNB1c.-48-3dupUncertain significance
Print report
Variant interpretation report

CTNNB1 c.-48-3dup, p.?

NM_001904.4:c.-48-3dup NP_001895.1:p.? 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
PM2Supporting
PM2 · supporting

This variant is present in gnomAD v4.1 at an extremely low allele frequency of 5.67×10⁻⁶ (9/1,586,636 alleles, 0.00057%), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. 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 supporting; combination = 1 supporting, 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.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV115288055, n = 1 times).

Context only COSMIC ↗
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 · 7 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001904.4:c.-48-3dupT is a single-nucleotide T duplication in the 5' UTR of CTNNB1, 48 bases upstream of the initiation codon. It is present in gnomAD v4.1 at an extremely low allele frequency of 0.00057% (9/1,586,636 alleles, no homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada v1.0.

The variant is absent from ClinVar and has not been reported in the published literature. No functional studies, segregation data, de novo observations, or case-control comparisons are available. SpliceAI predicts no significant splicing impact (max delta = 0.01).

The variant has been observed once in somatic cancers (COSMIC COSV115288055), but this does not inform germline pathogenicity.

Only PM2 (supporting) is met. With only one supporting pathogenic criterion and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic rules.

Met · 1

PM2 SupportingThis variant is present in gnomAD v4.1 at an extremely low allele frequency of 5.67×10⁻⁶ (9/1,586,636 alleles, 0.00057%), well below the 0.1% threshold for PM2. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0. No homozygotes observed. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 5.67e-06 (9/1
  • 586
  • 636)
  • absent from gnomAD v2.1 and gnomAD-Canada
  • 0 homozygotes
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 7 · evaluated, threshold not reached

PM1 The variant is located in the 5' UTR (c.-48-3dup), not within a known mutational hotspot or critical functional domain of CTNNB1. Hotspot analysis did not identify this residue as significant. Details ▾Hide ▴
Evidence considered
  • 5' UTR location
  • residue_significant=false in hotspot analysis
PP3 Multiple lines of computational evidence supporting a deleterious effect are required. SpliceAI predicts no significant splice impact (max delta = 0.01). REVEL and BayesDel scores are unavailable (not an SNV). HCI prior probability is not supported for CTNNB1. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splice impact)
  • REVEL/BayesDel unavailable
  • HCI prior not supported
Sources
spliceai ↗
PP5 This variant is absent from ClinVar. No reputable source (expert panel, clinical laboratory, or published report) has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no expert panel or clinical laboratory classification
Sources
clinvar ↗
BA1 Allele frequency in gnomAD v4.1 is 5.67×10⁻⁶ (0.00057%), far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00057%
  • well below 1%
Sources
gnomad_v4 ↗
BS1 Allele frequency in gnomAD v4.1 is 5.67×10⁻⁶ (0.00057%), far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00057%
  • well below 0.3%
Sources
gnomad_v4 ↗
BP4 Multiple lines of computational evidence suggesting no impact are required. SpliceAI predicts no splice effect (delta = 0.01, one line of evidence). REVEL and BayesDel are unavailable (variant is not an SNV). A single computational data point is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (single line only)
  • REVEL/BayesDel unavailable
Sources
spliceai ↗
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo occurrence data available. No publications report this variant in a trio or family context. Details ▾Hide ▴
Still missing
  • No de novo data available
PS3 No well-established functional studies available for this variant. SpliceAI delta score of 0.01 does not constitute positive functional evidence of pathogenicity. No literature reports functional characterization of this specific 5' UTR duplication. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta = 0.01 (no predicted splice impact)
Still missing
  • No variant-specific functional studies
PS4 No case-control data available. Variant is absent from ClinVar and no published disease cohorts report this variant. Details ▾Hide ▴
Still missing
  • No affected vs. control prevalence data
PM6 No de novo occurrence data available. No publications report this variant as a confirmed or assumed de novo event. Details ▾Hide ▴
Still missing
  • No de novo data
PP1 No co-segregation data available. No family studies report this variant. Details ▾Hide ▴
Still missing
  • No segregation data
PP4 No patient phenotype or family history data specific to this variant are available. No case reports describe the clinical presentation of individuals carrying this variant. Details ▾Hide ▴
Still missing
  • No patient phenotype data
BS2 Nine alleles are observed in gnomAD v4.1, which excludes individuals with severe pediatric disease. However, without explicit confirmation that these carriers are healthy adults with full phenotypic ascertainment, BS2 cannot be reliably applied. CTNNB1 syndrome is a severe early-onset neurodevelopmental disorder where incomplete penetrance is not expected. Details ▾Hide ▴
Evidence considered
  • 9 alleles in gnomAD v4.1
  • no direct healthy-adult confirmation
Still missing
  • Phenotype confirmation of gnomAD carriers
Sources
gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional data
BS4 No non-segregation data available. No family studies report this variant. Details ▾Hide ▴
Still missing
  • No segregation data
BP2 No data on observation in trans with a pathogenic variant. No phase information available. Details ▾Hide ▴
Still missing
  • No trans phase data
BP5 No data on an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Still missing
  • No alternate-molecular-basis data
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant NM_001904.4:c.-48-3dup is a single-nucleotide duplication in the 5' UTR (c.-48-3dup), 48 bases upstream of the ATG start codon. It does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) per the ClinGen SVI PVS1 framework (PMC6185798). PVS1 is not applicable to non-coding variants of this type. Details ▾Hide ▴
Evidence considered
  • 5' UTR duplication
  • not a null variant
  • variant_bucket=other per pvs1_variant_assessment
Sources
pvs1_generic_framework ↗
PS1 N/APS1 requires a different nucleotide change at the same position with established pathogenicity. This is a duplication, not a substitution, and no pathogenic variant at this 5' UTR position has been identified. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant at this position in ClinVar
  • variant is a duplication not a substitution
Sources
clinvar ↗
PM3 N/ASkipped per adjudication instructions: trivially not applicable (CTNNB1-associated disorders follow autosomal dominant inheritance; PM3 applies to recessive disorders). Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants in coding regions. This is a single-nucleotide duplication in the 5' UTR (c.-48-3dup), outside the coding sequence, and does not alter protein length. Details ▾Hide ▴
Evidence considered
  • Non-coding 5' UTR duplication
  • not a protein-coding indel or stop-loss
PM5 N/APM5 requires a novel missense variant at the same amino acid residue as a known pathogenic missense variant. This variant is a 5' UTR duplication and does not encode an amino acid change. PM5 candidate harvesting was not applicable (eligible_for_classic_pm5_search=false). Details ▾Hide ▴
Evidence considered
  • Variant is not a missense change
  • no protein residue context
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a 5' UTR duplication, not a missense change. Details ▾Hide ▴
Evidence considered
  • Variant is not a missense change
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is a 5' UTR duplication, not a missense change. Details ▾Hide ▴
Evidence considered
  • Variant is not a missense change
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This is a single-nucleotide duplication in the 5' UTR, not an in-frame coding indel. Details ▾Hide ▴
Evidence considered
  • 5' UTR duplication
  • not a protein-coding in-frame indel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a 5' UTR duplication, not a synonymous substitution. Details ▾Hide ▴
Evidence considered
  • Variant is not a synonymous coding substitution
PS5 N/APS5 requires a different pathogenic variant at the same position with an established functional or clinical effect. No pathogenic variant at this 5' UTR position has been established. Details ▾Hide ▴
Evidence considered
  • No established pathogenic variant at c.-48 position
Sources
clinvar ↗

Identifiers

Gene
CTNNB1
Transcript
NM_001904.4
Coding (HGVS c.)
NM_001904.4:c.-48-3dup
Protein (HGVS p.)
NP_001895.1:p.?
GRCh38
chr3:41224011 C>CT
GRCh37
chr3:41265502 C>CT
COSMIC
COSV115288055

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 9 / 1,586,636 alleles AF 5.67e-06 · 0 homozygotes · FAF 3.67e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.7e-06 · 9 / 1,586,636 alleles · 0 hom · FAF 3.7e-06
European (non-Finnish)9 / 1,155,384 7.8e-06
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= 5.67238e-06; MAF= 0.00057%, 9/1586636 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.78962e-06; MAF= 0.00078%, 9/1155384 alleles, homozygotes = 0); grpmax FAF= 3.67e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +232 bp
0.000
SpliceAI acceptor gainat +21 bp
0.000
SpliceAI donor lossat +76 bp
0.000
SpliceAI donor gainat -114 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple lines of computational evidence supporting a deleterious effect are required. SpliceAI predicts no significant splice impact (max delta = 0.01). REVEL and BayesDel scores are unavailable (not an SNV). HCI prior probability is not supported for CTNNB1. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (no splice impact)
  • REVEL/BayesDel unavailable
  • HCI prior not supported
Sources
spliceai ↗
BP4 Multiple lines of computational evidence suggesting no impact are required. SpliceAI predicts no splice effect (delta = 0.01, one line of evidence). REVEL and BayesDel are unavailable (variant is not an SNV). A single computational data point is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.01 (single line only)
  • REVEL/BayesDel unavailable
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a 5' UTR duplication, not a synonymous substitution. Details ▾Hide ▴
Evidence considered
  • Variant is not a synonymous coding substitution

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 9 / 1,586,636 recorded alleles 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 ↗

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= 5.67238e-06; MAF= 0.00057%, 9/1586636 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.78962e-06; MAF= 0.00078%, 9/1155384 alleles, homozygotes = 0); grpmax FAF= 3.67e-06.

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).

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV115288055, n = 1 times).