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.1239C>T (p.Tyr413Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 37/277230 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001207 (29/24032). 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 (PMID: 30311375)
"This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (9 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The variant CDH1 Y413= is a synonymous mutation and has not been functionally characterized.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -16 bp |
| Donor Loss (DL) | 0.0 | 81 bp |
| Acceptor Gain (AG) | 0.0 | 50 bp |
| Donor Gain (DG) | 0.0 | 247 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 or multi exon deletion) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: it is a synonymous (Y413=) change with no impact on canonical splice sites. Therefore, this criterion is not applied at Not Applied strength because the variant does not introduce a null 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: it is synonymous and does not change the amino acid. Therefore, this criterion is not applied at Not Applied strength because there is no amino acid change.
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 occurrence. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be confirmed.
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 have been performed. Therefore, this criterion is not applied at Not Applied strength because there is no functional evidence.
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 with the prevalence in controls". The evidence for this variant shows: no case–control or affected cohort data are available. Therefore, this criterion is not applied at Not Applied strength because prevalence in affected versus controls cannot be assessed.
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 (e.g., active site of an enzyme) without benign variation". The evidence for this variant shows: it is a synonymous change outside of any known functional domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not located in a mutational hot spot or critical domain.
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: MAF=0.0134% in gnomAD (38/282,890 alleles, no homozygotes), including 0.112% in African/African American, meeting rarity thresholds. Therefore, this criterion is applied at Moderate strength because the variant is absent or 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 an autosomal dominant gene and no trans data are relevant. Therefore, this criterion is not applied at Not Applied strength because PM3 is not applicable.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants". The evidence for this variant shows: it is a synonymous substitution with no protein length change. Therefore, this criterion is not applied at Not Applied strength because there is no alteration in protein length.
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: it is synonymous, not a missense change. Therefore, this criterion is not applied at Not Applied strength because PM5 is not relevant.
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 information on inheritance. Therefore, this criterion is not applied at Not Applied strength because de novo status is not documented.
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 family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation has not been assessed.
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 where missense variants are a common mechanism of disease". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength because PP2 is not applicable.
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 (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: in silico tools (CADD=0.27; SpliceAI=0.01) predict no deleterious effect. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support deleterious impact.
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 family history data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be evaluated.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: no reputable source reports this variant as pathogenic. Therefore, this criterion is not applied at Not Applied strength because no pathogenic assertion exists.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The evidence for this variant shows: MAF=0.0134%, well below 5%. Therefore, this criterion is not applied at Not Applied strength because the frequency does not exceed BA1 threshold.
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 (0.0134%), below expected thresholds. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not in excess.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) disorder, with full penetrance expected at an early age". The evidence for this variant shows: no documented observation in well-characterized healthy individuals. Therefore, this criterion is not applied at Not Applied strength because BS2 cannot be assessed.
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 function or splicing". The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied at Not Applied strength because functional assays are lacking.
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 available. Therefore, this criterion is not applied at Not Applied strength because segregation information is absent.
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: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength because BP1 is not relevant.
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 data on co-occurrence with pathogenic variants. Therefore, this criterion is not applied at Not Applied strength because BP2 cannot be evaluated.
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: it is a single nucleotide synonymous substitution. Therefore, this criterion is not applied at Not Applied strength because BP3 is not applicable.
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.)". The evidence for this variant shows: in silico predictors (CADD=0.27) and SpliceAI=0.01 predict no deleterious effect or splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence supports benign 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 reported. Therefore, this criterion is not applied at Not Applied strength because BP5 cannot be assessed.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: multiple ClinVar submissions classify it as Likely benign or Benign. Therefore, this criterion is applied at Supporting strength because a reputable source reports benign classification without primary evidence available.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site, and the nucleotide is not highly conserved". The evidence for this variant shows: SpliceAI=0.01 predicts no splice impact and it is synonymous. Therefore, this criterion is applied at Supporting strength because it is a silent change with no predicted splicing effect.