rs730881655

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6_Very_StrongBS2_Supporting

The NM_004360.5(CDH1):​c.48+15_48+16delCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000963 in 1,536,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 37)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CDH1
NM_004360.5 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0460
Variant links:
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 16-68737477-CCT-C is Benign according to our data. Variant chr16-68737477-CCT-C is described in ClinVar as [Likely_benign]. Clinvar id is 182378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.48+15_48+16delCT intron_variant ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61
CDH1NM_001317184.2 linkuse as main transcriptc.48+15_48+16delCT intron_variant NP_001304113.1 P12830-2B3GN61
CDH1NM_001317185.2 linkuse as main transcriptc.-1568+15_-1568+16delCT intron_variant NP_001304114.1 P12830B3GN61Q9UII7
CDH1NM_001317186.2 linkuse as main transcriptc.-1772+15_-1772+16delCT intron_variant NP_001304115.1 P12830B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.48+15_48+16delCT intron_variant 1 NM_004360.5 ENSP00000261769.4 P12830-1
CDH1ENST00000422392.6 linkuse as main transcriptc.48+15_48+16delCT intron_variant 1 ENSP00000414946.2 P12830-2
CDH1ENST00000566612.5 linkuse as main transcriptn.48+15_48+16delCT intron_variant 1 ENSP00000454782.1 H3BNC6
CDH1ENST00000566510.5 linkuse as main transcriptn.48+15_48+16delCT intron_variant 5 ENSP00000458139.1 H3BVI7

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152174
Hom.:
0
Cov.:
37
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000387
AC:
5
AN:
129344
Hom.:
0
AF XY:
0.0000561
AC XY:
4
AN XY:
71242
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000822
Gnomad OTH exome
AF:
0.000251
GnomAD4 exome
AF:
0.000100
AC:
139
AN:
1384090
Hom.:
0
AF XY:
0.0000907
AC XY:
62
AN XY:
683590
show subpopulations
Gnomad4 AFR exome
AF:
0.0000319
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000124
Gnomad4 OTH exome
AF:
0.0000692
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152174
Hom.:
0
Cov.:
37
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000793

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:2
Likely benign, criteria provided, single submitterclinical testingCounsylAug 01, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 13, 2016- -
Benign, criteria provided, single submitterclinical testingGeneDxOct 30, 2013The variant is found in BR-OV-HEREDIC,HIRISK-BR-HEREDIC panel(s). -
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 31, 2022- -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The CDH1 c.48+15_48+16del variant was not identified in the literature nor was it identified in the Zhejiang University database. The variant was identified in dbSNP (ID: rs730881655) as "With Likely benign allele", and in ClinVar (classified as benign by GeneDx; as likely benign by Counsyl, Color Genomics). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730881655; hg19: chr16-68771380; API