CTNNB1 c.1081+3A>C, p.?
NM_001904.4:c.1081+3A>C
Variant of Uncertain Significance (VUS)
This CTNNB1 c.1081+3A>C variant is absent from population databases (PM2) and computational predictions support no impact on splicing or protein function (BP4). No other evidence is available to support pathogenicity or benign impact, resulting in classification as Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
CTNNB1
Transcript
NM_001904.4
MANE Select
Total Exons
15
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001904.3 | Alternative | 15 exons | Forward |
Variant Details
HGVS Notation
NM_001904.4:c.1081+3A>C
Protein Change
?
Location
Exon 7
(Exon 7 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001904.4
Genome Browser
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HGVS InputNM_001904:c.1081+3A>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.56
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion)'. The variant is at the +3 splice position, not at a canonical +1 or +2 splice site and does not create a null allele. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. There is no known amino acid change or matching pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. No de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. No functional studies have been reported for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. No case-control or prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. This variant is at the +3 splice position, not within a known hotspot or functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The variant is absent from gnomAD, ExAC, 1000 Genomes, and other population databases. Therefore, this criterion is applied at Moderate strength because the variant is not found in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. CTNNB1-associated disease is dominant and no trans data exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. This variant is a splice region change, not an in-frame insertion/deletion. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The variant does not alter an amino acid residue. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. No de novo data exist. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 is: 'Co-segregation with disease in multiple affected family members'. No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. This is a splice region variant, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product'. In silico tools including CADD (2.56) and SpliceAI (0.09) do not predict a damaging effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology'. No phenotype or family history details are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The variant is not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 is: 'Allele frequency is too high for the disorder'. This variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 is: 'Allele frequency is greater than expected for disorder'. This variant is not observed in population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. No functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 is: 'Lack of segregation in affected family members'. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 is: 'Missense variant in a gene where only loss of function causes disease'. This is not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. This variant is not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)'. In silico tools including CADD (score 2.56) and SpliceAI (score 0.09) predict no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. No such cases are reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The variant is not reported as benign in any source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 is: 'Synonymous variant with no predicted impact on splicing'. This variant is intronic at +3, not synonymous. Therefore, this criterion is not applied.