16-68737366-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_004360.5(CDH1):c.-50C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000002 in 1,499,596 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: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Consequence
CDH1
NM_004360.5 5_prime_UTR
NM_004360.5 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.170
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=-0.57).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.-50C>T | 5_prime_UTR_variant | 1/16 | ENST00000261769.10 | ||
CDH1 | NM_001317184.2 | c.-50C>T | 5_prime_UTR_variant | 1/15 | |||
CDH1 | NM_001317185.2 | c.-1665C>T | 5_prime_UTR_variant | 1/16 | |||
CDH1 | NM_001317186.2 | c.-1869C>T | 5_prime_UTR_variant | 1/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.-50C>T | 5_prime_UTR_variant | 1/16 | 1 | NM_004360.5 | P1 | ||
CDH1 | ENST00000422392.6 | c.-50C>T | 5_prime_UTR_variant | 1/15 | 1 | ||||
CDH1 | ENST00000566612.5 | c.-50C>T | 5_prime_UTR_variant, NMD_transcript_variant | 1/15 | 1 | ||||
CDH1 | ENST00000566510.5 | c.-50C>T | 5_prime_UTR_variant, NMD_transcript_variant | 1/15 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000148 AC: 2AN: 1347364Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 666006
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2017 | This variant is denoted CDH1 c.-50C>T, and describes a nucleotide substitution 50 base pairs upstream of the ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is GGCC[C/T]GACC. This variant does not appear to affect the start codon or the Kozak translational consensus sequence, and it is not predicted to affect splicing. The cytosine (C) nucleotide that is altered is not conserved across species. CDH1 c.-50C>T was not observed in large population cohorts; however, limited data are available (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Although this particular variant has not, to our knowledge, been published in the literature, variants have been reported in this region at c.-49 and c.-54 per HGMD (Stenson 2013). Luciferase reporter assays showed that c.-49G>T contributes to a slight increase in promoter activity, while c.-54G>C significantly decreases (p = 0.003) promoter activity (Nakamura 2002, Chen 2013). Based on currently available information, it is unclear whether CDH1 c.-50C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 21, 2023 | The c.-50C>T variant occurs in the 5'UTR. This variant has an allele frequency of 0.00001 (1 in 151,862) in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>T variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID: 23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. - |
Computational scores
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BayesDel_noAF
Benign
Cadd
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Dann
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Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at