CTNNB1 c.937-10_937-9del, p.?
NM_001904.4:c.937-10_937-9del
COSMIC ID: COSN15649848, COSN30726950
Variant of Uncertain Significance (VUS)
This intronic CTNNB1 variant is outside canonical splice sites, has a population frequency of 0.152%, lacks functional or segregation data, and is predicted by computational tools to have no impact (BP4). No other criteria apply, resulting in a classification of VUS.
ACMG/AMP Criteria Applied
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.937-10_937-9del
Protein Change
?
Location
Exon 6
(Exon 6 of 15)
5'Exon Structure (15 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN15649848, COSN30726950
Variant interpretation based on transcript NM_001904.4
Genome Browser
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HGVS InputNM_001904:c.937-10_937-9del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.152%
Common
Highest in Population
European (Finnish)
0.378%
Common
Global: 0.152%
European (Finnish): 0.378%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 214004Alt: 326Homozygotes: 0
ACMG Criteria Applied
None
This variant is present in gnomAD (MAF= 0.152%, 326/214004 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.378%, 66/17462 alleles, homozygotes = 0). The variant frequency does not support application of PM2, BA1, or BS1 criteria.
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
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 rule is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease". The evidence for this variant shows: it is an intronic deletion (c.937-10_937-9del) outside of the canonical ±1 or 2 splice sites and is not predicted to abolish splicing. Therefore, this criterion is not applied because the variant does not create a null effect at canonical splice sites or other LoF mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 rule is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: it is intronic and does not result in any amino acid change. Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: de novo status has not been established. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 rule is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because functional data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 rule is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control data or excess in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 rule is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: it is an intronic deletion not within any functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM2 rule is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is present in gnomAD with a MAF of 0.152%. Therefore, this criterion is not applied because the variant is not absent or at extremely low frequency.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 rule is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: CTNNB1-related disorder is dominant, and no trans data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 rule is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is intronic and does not change protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 rule is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is intronic, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 rule is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 rule is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 rule is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: SpliceAI predicts no impact (score 0) and no other in silico tool predicts deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 rule is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 rule is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 rule is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF is 0.152%, below 5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 rule is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: frequency does not clearly exceed the maximum credible frequency threshold for CTNNB1-related disorders. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 rule is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no specific healthy individual observations documented. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 rule is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 rule is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 rule is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 rule is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 rule is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is not in-frame and not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 rule is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: SpliceAI predicts no impact on splicing (score 0) and no deleterious in silico predictions. Therefore, this criterion is applied at Supporting strength because computational tools uniformly predict no functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 rule is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 rule is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 rule is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is intronic, not synonymous. Therefore, this criterion is not applied.