rs1205684749
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_004360.5(CDH1):c.163+4_163+6dup variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,536,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000051 ( 0 hom. )
Consequence
CDH1
NM_004360.5 splice_region, intron
NM_004360.5 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.592
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 -8 ACMG points.
BP6
?
Variant 16-68738413-T-TGAG is Benign according to our data. Variant chr16-68738413-T-TGAG is described in ClinVar as [Likely_benign]. Clinvar id is 186186.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.163+4_163+6dup | splice_region_variant, intron_variant | ENST00000261769.10 | |||
CDH1 | NM_001317184.2 | c.163+4_163+6dup | splice_region_variant, intron_variant | ||||
CDH1 | NM_001317185.2 | c.-1453+4_-1453+6dup | splice_region_variant, intron_variant | ||||
CDH1 | NM_001317186.2 | c.-1657+4_-1657+6dup | splice_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.163+4_163+6dup | splice_region_variant, intron_variant | 1 | NM_004360.5 | P1 | |||
CDH1 | ENST00000422392.6 | c.163+4_163+6dup | splice_region_variant, intron_variant | 1 | |||||
CDH1 | ENST00000566612.5 | c.163+4_163+6dup | splice_region_variant, intron_variant, NMD_transcript_variant | 1 | |||||
CDH1 | ENST00000566510.5 | c.163+4_163+6dup | splice_region_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151804Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000134 AC: 2AN: 149510Hom.: 0 AF XY: 0.0000126 AC XY: 1AN XY: 79410
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GnomAD4 exome AF: 0.00000506 AC: 7AN: 1384118Hom.: 0 Cov.: 28 AF XY: 0.00000440 AC XY: 3AN XY: 681940
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151922Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
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ClinVar
Significance: Likely benign
Submissions summary: Benign:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jul 22, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 03, 2023 | This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 06, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 17, 2023 | The CDH1 c.163+4_163+6dupAGG variant occurs in the splice donor region of intron 2. This allele is present at a frequency of 0.00001338 (2 in 149,510 alleles) in the gnomAD database (GRCh37) (http://gnomad.broadinstitute.org). This variant has been observed in more than ten individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000969083.1, SCV000216473.4, SCV000637738.2). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2023 | 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. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at