Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001904.3 | Alternative | 3720 nt | 269–2614 |
| NM_001904.4 | MANE Select | 3661 nt | 215–2560 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -188 bp |
| Donor Loss (DL) | 0.0 | -18 bp |
| Acceptor Gain (AG) | 0.02 | 51 bp |
| Donor Gain (DG) | 0.01 | -20 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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." The evidence for this variant shows: NM_001904.4:c.1954+14A>G is an intronic variant at position +14, outside the canonical ±1/2 splice sites and does not create a stop or frameshift. Therefore, this criterion is not applied because the variant does not meet the definition of a LoF null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no protein change has been defined for this intronic alteration and no matching amino acid change is reported. Therefore, this criterion is not applied because there is no established amino acid change to compare.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no data on de novo status or parental testing are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 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 evidence is lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case-control or prevalence data are available. Therefore, this criterion is not applied due to absence of statistical association data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation." The evidence for this variant shows: the +14 intronic location is not within a known hotspot or functional domain. Therefore, this criterion is not applied because no hotspot or critical domain is implicated.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows: it is not present in gnomAD, ExAC, 1000 Genomes, or ESP. Therefore, this criterion is applied at Moderate strength because the variant is absent from large control populations.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: CTNNB1-related disorders are typically haploinsufficiency and there is no evidence of trans configuration with another pathogenic allele. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: no coding in-frame insertion/deletion or stop-loss effect. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: no missense or amino acid residue change is described. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no evidence of de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease." The evidence for this variant shows: it is intronic with no missense effect. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product." The evidence for this variant shows: in silico tools (CADD 0.95, SpliceAI 0.02) predict no impact. Therefore, this criterion is not applied because computational predictions are benign.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or clinical information provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports the variant as pathogenic, but without accessible evidence." The evidence for this variant shows: not found in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder." The evidence for this variant shows: absent from population databases, frequency is not high. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy adult individuals for dominant disorders with full penetrance." The evidence for this variant shows: no healthy individual case data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional assays available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 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 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or cis with another pathogenic variant." The evidence for this variant shows: no such configuration data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
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." The evidence for this variant shows: CADD score 0.95 and SpliceAI 0.02 predict minimal impact. Therefore, this criterion is applied at Supporting strength because computational tools consistently predict benign effect.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 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 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence." The evidence for this variant shows: not reported in any database as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing." The evidence for this variant shows: it is intronic rather than synonymous. Therefore, this criterion is not applied.