Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_004360.3 | Alternative | 4815 nt | 125–2773 |
| NM_004360.5 | MANE Select | 4811 nt | 125–2773 |
| NM_004360.4 | Alternative | 4845 nt | 127–2775 |
| NM_004360.2 | Alternative | 4828 nt | 125–2773 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenVariant summary: The CDH1 c.1138-3C>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 36/277198 control chromosomes from all ethnicities, but was predominantly observed in the African subpopulation at a frequency of 0.001207 (29/24036). This frequency is about 43 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign or likely benign. Taken together, this variant is classified as benign.
BS1; BP4 (PMID: 30311375)
The c.1138-3C>T variant has an allele frequency of 0.00121 (0.121%, 29/24,036 alleles) in the African subpopulation of the gnomAD cohort (BS1). There are at least 3 in silico predictors in agreement that this variant does not affect splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BP4 (Variant Interpretation Guidelines Version 3.1).
"This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (7 clinical laboratories) and as Likely benign by Clingen Gastric Cancer Variant Curation Expert Panel expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 3 bp |
| Donor Loss (DL) | 0.0 | 185 bp |
| Acceptor Gain (AG) | 0.01 | 88 bp |
| Donor Gain (DG) | 0.0 | -235 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single/multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: c.1138-3C>T is an intronic variant at position -3 relative to the exon and SpliceAI predicts no impact on splicing. Therefore, this criterion is not applied because the variant does not disrupt canonical splice sites or create a predicted loss-of-function effect.
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 amino acid change (intronic) and no known pathogenic variant at this position. Therefore, this criterion is not applied.
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 de novo data available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to controls.' The evidence for this variant shows: no case-control data available demonstrating enrichment. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain, without benign variation.' The evidence for this variant shows: position c.1138-3 is not within a defined hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.' The evidence for this variant shows: present in gnomAD at MAF=0.0131%, extremely low frequency and no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: CDH1 is autosomal dominant and no trans-phase data. 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 in a non-repeat region or stop-loss variants.' The evidence for this variant shows: no change in protein length (intronic). 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 missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: not a missense variant. 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 de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.' The evidence for this variant shows: intronic change, not missense. 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 or gene product.' The evidence for this variant shows: computational tools (SpliceAI max delta score 0.01, CADD 1.41) predict no impact. Therefore, this criterion is not applied.
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/family history data. 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 the evidence is not available to the laboratory.' The evidence for this variant shows: ClinVar reports benign/likely benign only. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is >5% in population databases.' The evidence for this variant shows: MAF=0.0131%, well below threshold. 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 disorder.' The evidence for this variant shows: frequency is low and within expected limits for CDH1. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a fully penetrant dominant disorder.' The evidence for this variant shows: no data on healthy adult heterozygotes. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies show no damaging effect on protein.' The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family.' The evidence for this variant shows: no 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 for which primarily truncating variants are known to cause disease.' The evidence for this variant shows: intronic change. 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 a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.' The evidence for this variant shows: no phase 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 a 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: SpliceAI max score 0.01 and low CADD score, indicating no deleterious effect. Therefore, this criterion is applied at Supporting strength because in silico tools predict no impact.
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 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports benign, but no evidence available.' The evidence for this variant shows: ClinVar reports as Benign/Likely benign across multiple laboratories and the ClinGen CDH1 Panel calls it Likely benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'A synonymous variant for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved.' The evidence for this variant shows: intronic change, not synonymous. Therefore, this criterion is not applied.