16-68815553-C-T
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001317185.2(CDH1):c.-190C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000078 ( 1 hom. )
Consequence
CDH1
NM_001317185.2 5_prime_UTR_premature_start_codon_gain
NM_001317185.2 5_prime_UTR_premature_start_codon_gain
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.74
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 16-68815553-C-T is Benign according to our data. Variant chr16-68815553-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 184324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68815553-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000078 (114/1461880) while in subpopulation AMR AF= 0.00116 (52/44724). AF 95% confidence interval is 0.00091. There are 1 homozygotes in gnomad4_exome. There are 59 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH1 | NM_004360.5 | c.1359C>T | p.His453His | synonymous_variant | Exon 10 of 16 | ENST00000261769.10 | NP_004351.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152232Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000247 AC: 62AN: 251478Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135916
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GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461880Hom.: 1 Cov.: 32 AF XY: 0.0000811 AC XY: 59AN XY: 727238
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GnomAD4 genome 0.0000919 AC: 14AN: 152350Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74508
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 13, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 25, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 22, 2018 | Variant summary: CDH1 c.1359C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 277242 control chromosomes. The observed variant frequency is approximately 9-fold above the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. c.1359C>T has been reported in the literature as a somatic mutation in a colorectal tumor, and thus does not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Hereditary diffuse gastric adenocarcinoma Benign:4
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | - - |
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 06, 2023 | This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2014 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 04, 2015 | - - |
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 09, 2021 | - - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 15, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 03, 2022 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Nov 11, 2024 | According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): No predicted impact on splicing, BP7 (supporting benign): The variation shows a not conserved nucleotide (phyloP: -1.46 [-19.0, 10.9])., BS1 (strong benign): gnomAD v3: East Asian: 0.1347% - |
Computational scores
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Name
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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