16-68801894-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_004360.5(CDH1):c.387+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_004360.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.387+1G>C | splice_donor_variant, intron_variant | Intron 3 of 15 | ENST00000261769.10 | NP_004351.1 | ||
CDH1 | NM_001317184.2 | c.387+1G>C | splice_donor_variant, intron_variant | Intron 3 of 14 | NP_001304113.1 | |||
CDH1 | NM_001317185.2 | c.-1229+1G>C | splice_donor_variant, intron_variant | Intron 3 of 15 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1433+1G>C | splice_donor_variant, intron_variant | Intron 3 of 14 | NP_001304115.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1
This sequence change affects a donor splice site in intron 3 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 664945). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 31642931; Invitae; Poster G20 in http://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at