rs730881655
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6_Very_StrongBS2_Supporting
The NM_004360.5(CDH1):c.48+15_48+16delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000963 in 1,536,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 37)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
CDH1
NM_004360.5 intron
NM_004360.5 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0460
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 -9 ACMG points.
BP6
Variant 16-68737477-CCT-C is Benign according to our data. Variant chr16-68737477-CCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 182378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.48+15_48+16delCT | intron_variant | ENST00000261769.10 | NP_004351.1 | |||
CDH1 | NM_001317184.2 | c.48+15_48+16delCT | intron_variant | NP_001304113.1 | ||||
CDH1 | NM_001317185.2 | c.-1568+15_-1568+16delCT | intron_variant | NP_001304114.1 | ||||
CDH1 | NM_001317186.2 | c.-1772+15_-1772+16delCT | intron_variant | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.48+15_48+16delCT | intron_variant | 1 | NM_004360.5 | ENSP00000261769.4 | ||||
CDH1 | ENST00000422392.6 | c.48+15_48+16delCT | intron_variant | 1 | ENSP00000414946.2 | |||||
CDH1 | ENST00000566612.5 | n.48+15_48+16delCT | intron_variant | 1 | ENSP00000454782.1 | |||||
CDH1 | ENST00000566510.5 | n.48+15_48+16delCT | intron_variant | 5 | ENSP00000458139.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152174Hom.: 0 Cov.: 37
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GnomAD3 exomes AF: 0.0000387 AC: 5AN: 129344Hom.: 0 AF XY: 0.0000561 AC XY: 4AN XY: 71242
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GnomAD4 exome AF: 0.000100 AC: 139AN: 1384090Hom.: 0 AF XY: 0.0000907 AC XY: 62AN XY: 683590
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152174Hom.: 0 Cov.: 37 AF XY: 0.0000269 AC XY: 2AN XY: 74342
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Aug 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 13, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2013 | The variant is found in BR-OV-HEREDIC,HIRISK-BR-HEREDIC panel(s). - |
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2022 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 c.48+15_48+16del variant was not identified in the literature nor was it identified in the Zhejiang University database. The variant was identified in dbSNP (ID: rs730881655) as "With Likely benign allele", and in ClinVar (classified as benign by GeneDx; as likely benign by Counsyl, Color Genomics). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at