rs786201853
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_Very_StrongBP7BS2_Supporting
The NM_004360.5(CDH1):āc.2352T>Cā(p.Arg784=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,876 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 Likely benign (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000048 ( 0 hom. )
Consequence
CDH1
NM_004360.5 synonymous
NM_004360.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.24
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 -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
?
Variant 16-68829710-T-C is Benign according to our data. Variant chr16-68829710-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 184996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-1.24 with no splicing effect.
BS2
?
High AC in GnomAdExome4 at 7 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 | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2352T>C | p.Arg784= | synonymous_variant | 15/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2169T>C | p.Arg723= | synonymous_variant | 14/15 | ||
CDH1 | NM_001317185.2 | c.804T>C | p.Arg268= | synonymous_variant | 15/16 | ||
CDH1 | NM_001317186.2 | c.387T>C | p.Arg129= | synonymous_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2352T>C | p.Arg784= | synonymous_variant | 15/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727242
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 30, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2018 | 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. - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 27, 2022 | - - |
Hereditary diffuse gastric adenocarcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
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 p.Arg784= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs768796172) as "With Likely benign allele" and in ClinVar (classified as likely benign by Invitae and Ambry Genetics). The variant was identified in control databases in 1 of 246250 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111708 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg784= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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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