rs139757930
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004360.5(CDH1):c.2440-6C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,682 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_004360.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2440-6C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000261769.10 | |||
CDH1 | NM_001317184.2 | c.2257-6C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH1 | NM_001317185.2 | c.892-6C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
CDH1 | NM_001317186.2 | c.475-6C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2440-6C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00150 AC: 229AN: 152166Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00180 AC: 453AN: 251368Hom.: 2 AF XY: 0.00175 AC XY: 238AN XY: 135898
GnomAD4 exome AF: 0.00133 AC: 1940AN: 1461398Hom.: 4 Cov.: 32 AF XY: 0.00137 AC XY: 997AN XY: 727024
GnomAD4 genome ? AF: 0.00150 AC: 229AN: 152284Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115AN XY: 74452
ClinVar
Submissions by phenotype
not specified Benign:7
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 01, 2017 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 04, 2020 | - - |
not provided Benign:7
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 08, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | CDH1: BP4, BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2016 | Variant summary: Variant affects a non-conserved intronic nucleotide located at a position not widely known to affect splicing. Mutation taster predicts the variant to be neutral along with 5/5 in silico tools via Alamut predicting no significant effect on normal splicing by the variant. The variant was in the large and broad cohorts of the ExAC project at an allele frequency of o,1% which is 63 times higher than the maximal expected allele frequency of a disease causing CDH1 allele (0.0028%) indicating a neutral impact. The variant showed lack of co-segregation with HDGC in one family (Grodecka_GCC_2014) and was shown not to affect splicing and the expression level of the protein (Grodecka_GCC_2014; Molinaro_GCC_2014) further supporting a benign nature. Additionally, clinical diagnostic centers classify variant as Likely Benign/Benign (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign. - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary cancer-predisposing syndrome Benign:5
Likely benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 14, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Nov 15, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2021 | 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 10, 2020 | - - |
Hereditary diffuse gastric adenocarcinoma Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | BS1; BS2; BS3; BP4 (PMID: 30311375) - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 24, 2019 | - - |
Malignant tumor of prostate Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
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.2440-6C>G variant was identified in 3 of 462 proband chromosomes (frequency: 0.006) from individuals or families with diffuse gastric and lung cancer (Guilford 2007, More 2007, Yorczyk 2015). The variant was also identified in the following databases: dbSNP (ID: rs139757930) as With Likely benign, ClinVar (classified as benign by Invitae, as likely benign by GeneDx and Ambry Genetics), Clinvitae (classified as likely benign by ClinVar, Invitae), Insight Colon Cancer Gene Variant Database (1X), and the Zhejiang Colon Cancer Database. The variant was identified in control databases in 453 (1 homozygous) of 277200 chromosomes at a frequency of 0.0016 in the following populations: European in 215 of 126702 chromosomes (freq. 0.002), Latino in 126 of 34420 chromosomes (freq. 0.004), Ashkenazi Jewish in 73 of 10152 chromosomes (freq. 0.007), Other in 29 of 6466 chromosomes (freq. 0.004), South Asian in 6 of 30782 chromosomes (freq.0.0002), African in 4 of 24024 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The c.2440-6C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. There is conflicting evidence in the literature regarding effect on splicing. The variant causes abnormal RNA transcripts compared to RNA from a healthy unrelated control Individuals in More et al. (2007), while in Grodeck√° (2014) results showed mostly correctly spliced transcripts of both wild type and c.2440-6C>G variants. 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at