16-68737408-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_004360.5(CDH1):c.-8G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,378,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Consequence
CDH1
NM_004360.5 5_prime_UTR
NM_004360.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.152
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.-8G>A | 5_prime_UTR_variant | 1/16 | ENST00000261769.10 | ||
CDH1 | NM_001317184.2 | c.-8G>A | 5_prime_UTR_variant | 1/15 | |||
CDH1 | NM_001317185.2 | c.-1623G>A | 5_prime_UTR_variant | 1/16 | |||
CDH1 | NM_001317186.2 | c.-1827G>A | 5_prime_UTR_variant | 1/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.-8G>A | 5_prime_UTR_variant | 1/16 | 1 | NM_004360.5 | P1 | ||
CDH1 | ENST00000422392.6 | c.-8G>A | 5_prime_UTR_variant | 1/15 | 1 | ||||
CDH1 | ENST00000566612.5 | c.-8G>A | 5_prime_UTR_variant, NMD_transcript_variant | 1/15 | 1 | ||||
CDH1 | ENST00000566510.5 | c.-8G>A | 5_prime_UTR_variant, NMD_transcript_variant | 1/15 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000790 AC: 1AN: 126528Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 69612
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GnomAD4 exome AF: 0.00000290 AC: 4AN: 1378874Hom.: 0 Cov.: 30 AF XY: 0.00000294 AC XY: 2AN XY: 680406
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 22, 2017 | Variant summary: The CDH1 c.-8G>A variant involves the alteration of a non-conserved 5' UTR nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 1/121892 control chromosomes (gnomAD) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 12, 2021 | This variant is located in the 5' untranslated region of the CDH1 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/126528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at