chr16-68737468-C-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2BA1
This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.48+5C>G variant has an allele frequency of 0.11584 (11.584%, 1670/14416 alleles, 98 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA163551/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CDH1 | NM_004360.5 | c.48+5C>G | splice_region_variant, intron_variant | Intron 1 of 15 | ENST00000261769.10 | NP_004351.1 | ||
CDH1 | NM_001317184.2 | c.48+5C>G | splice_region_variant, intron_variant | Intron 1 of 14 | NP_001304113.1 | |||
CDH1 | NM_001317185.2 | c.-1568+5C>G | splice_region_variant, intron_variant | Intron 1 of 15 | NP_001304114.1 | |||
CDH1 | NM_001317186.2 | c.-1772+5C>G | splice_region_variant, intron_variant | Intron 1 of 14 | NP_001304115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.48+5C>G | splice_region_variant, intron_variant | Intron 1 of 15 | 1 | NM_004360.5 | ENSP00000261769.4 | |||
CDH1 | ENST00000422392.6 | c.48+5C>G | splice_region_variant, intron_variant | Intron 1 of 14 | 1 | ENSP00000414946.2 | ||||
CDH1 | ENST00000566612.5 | n.48+5C>G | splice_region_variant, intron_variant | Intron 1 of 14 | 1 | ENSP00000454782.1 | ||||
CDH1 | ENST00000566510.5 | n.48+5C>G | splice_region_variant, intron_variant | Intron 1 of 14 | 5 | ENSP00000458139.1 |
Frequencies
GnomAD3 genomes AF: 0.0325 AC: 4951AN: 152192Hom.: 277 Cov.: 33
GnomAD3 exomes AF: 0.00637 AC: 836AN: 131340Hom.: 32 AF XY: 0.00499 AC XY: 361AN XY: 72348
GnomAD4 exome AF: 0.00321 AC: 4450AN: 1385290Hom.: 233 Cov.: 30 AF XY: 0.00286 AC XY: 1955AN XY: 684218
GnomAD4 genome AF: 0.0326 AC: 4968AN: 152308Hom.: 276 Cov.: 33 AF XY: 0.0320 AC XY: 2386AN XY: 74478
ClinVar
Submissions by phenotype
not specified Benign:7
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Hereditary diffuse gastric adenocarcinoma Benign:5
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. -
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BA1; BP2_Strong (PMID: 30311375) -
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This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
not provided Benign:4
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Hereditary cancer-predisposing syndrome Benign:3
This alteration is classified as 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. -
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Breast and/or ovarian cancer Benign:1
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Prostate cancer Benign:1
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CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
The NM_004360.5(CDH1):c.48+5C>G variant has an allele frequency of 0.11584 (11.584%, 1670/14416 alleles, 98 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. -
Malignant tumor of breast Benign:1
The CDH1 c.48+5C>G variant was identified in 1 of 56 proband chromosomes (frequency: 0.02) from individuals or families with gastric cancer and was not identified in 200 control chromosomes from healthy individuals (Oliveira 2002). The variant was also identified in the following databases: dbSNP (ID: rs77312180) as With Benign allele, ClinVar (classified as benign by Ambry Genetics, Prevention Genetics, Invitae), Clinvitae (classified as benign by ClinVar and Invitae), and Zhejiang Colon Cancer databases. The variant was not identified in Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 1855 (97 homozygous) of 157630 chromosomes at a frequency of 0.012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1636 of 14186 chromosomes (freq: 0.115). The c.48+5C>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at