rs876661118
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004360.5(CDH1):βc.1779delβ(p.Ile594TyrfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. A592A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004360.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1779del | p.Ile594TyrfsTer19 | frameshift_variant | 12/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.1596del | p.Ile533TyrfsTer19 | frameshift_variant | 11/15 | ||
CDH1 | NM_001317185.2 | c.231del | p.Ile78TyrfsTer19 | frameshift_variant | 12/16 | ||
CDH1 | NM_001317186.2 | c.-187del | 5_prime_UTR_variant | 11/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1779del | p.Ile594TyrfsTer19 | frameshift_variant | 12/16 | 1 | NM_004360.5 | P1 | |
ENST00000563916.1 | n.263+1200del | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 14, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has not been reported in the literature in individuals with CDH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile594Tyrfs*19) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at