16-68815553-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001317185.2(CDH1):c.-190C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001317185.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1359C>T | p.His453His | synonymous_variant | Exon 10 of 16 | ENST00000261769.10 | NP_004351.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000247 AC: 62AN: 251478Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135916
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461880Hom.: 1 Cov.: 32 AF XY: 0.0000811 AC XY: 59AN XY: 727238
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152350Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74508
ClinVar
Submissions by phenotype
not specified Benign:4
- -
- -
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. -
Variant summary: CDH1 c.1359C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 277242 control chromosomes. The observed variant frequency is approximately 9-fold above the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. c.1359C>T has been reported in the literature as a somatic mutation in a colorectal tumor, and thus does not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Hereditary diffuse gastric adenocarcinoma Benign:4
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
- -
- -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Hereditary cancer-predisposing syndrome Benign:3
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. -
- -
- -
not provided Benign:2
- -
- -
Hereditary breast ovarian cancer syndrome Benign:1
According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): No predicted impact on splicing, BP7 (supporting benign): The variation shows a not conserved nucleotide (phyloP: -1.46 [-19.0, 10.9])., BS1 (strong benign): gnomAD v3: East Asian: 0.1347% -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at