rs1555509752
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_004360.5(CDH1):c.49-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,379,752 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 (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000065 ( 0 hom. )
Consequence
CDH1
NM_004360.5 splice_polypyrimidine_tract, intron
NM_004360.5 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.001651
2
Clinical Significance
Conservation
PhyloP100: 0.989
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 -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
?
Variant 16-68738288-C-A is Benign according to our data. Variant chr16-68738288-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 516511.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.49-9C>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000261769.10 | |||
CDH1 | NM_001317184.2 | c.49-9C>A | splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH1 | NM_001317185.2 | c.-1567-9C>A | splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH1 | NM_001317186.2 | c.-1771-9C>A | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.49-9C>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004360.5 | P1 | |||
CDH1 | ENST00000422392.6 | c.49-9C>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | |||||
CDH1 | ENST00000566612.5 | c.49-9C>A | splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | 1 | |||||
CDH1 | ENST00000566510.5 | c.49-9C>A | splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000652 AC: 9AN: 1379752Hom.: 0 Cov.: 28 AF XY: 0.00000587 AC XY: 4AN XY: 681906
GnomAD4 exome
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1379752
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28
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4
AN XY:
681906
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 c.49-9C>A variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (classified as uncertain significance by Invitae and likely benign by GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in an individual in our laboratory with a pathogenic POLE variant (c. c.5378+1G>A). The variant occurs at a non-highly conserved nucleotide and 2 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2018 | 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. - |
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 18, 2023 | The c.49-9C>A is an intronic variant in the splice acceptor region of intron 1. This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; SCV000729557.1, SCV000760811.1). This variant is predicted to have no impact on splicing by multiple in silico splice site predictors. HumanSpliceFinder predicts that this variant may alter an exonic ESE site, but this effect has not been demonstrated experimentally to our knowledge (BP4). In summary, due to the use of the Bayesian point system for this variant with conflicting evidence, this variant meets criteria to be 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): PM2_Supporting, BS2_Supporting, BP4. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 06, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at