16-68737515-C-CGCCCCAGCCCCGT

Variant names:

• chr16-68737515-C-CGCCCCAGCCCCGT
• rs45625236
• NM_004360.5:c.48+62_48+63insCGTGCCCCAGCCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004360.5(CDH1):​c.48+62_48+63insCGTGCCCCAGCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 1,350,920 control chromosomes in the GnomAD database, including 490,647 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (47790 hom., cov: 0)
  • Exomes 𝑓: 0.85 (442857 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.554
• Publications: 1 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-68737515-C-CGCCCCAGCCCCGT is Benign according to our data. Variant chr16-68737515-C-CGCCCCAGCCCCGT is described in ClinVar as Benign. ClinVar VariationId is 1243608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.48+62_48+63insCGTGCCCCAGCCC		intron_variant	Intron 1 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.48+62_48+63insCGTGCCCCAGCCC		intron_variant	Intron 1 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1568+62_-1568+63insCGTGCCCCAGCCC		intron_variant	Intron 1 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1772+62_-1772+63insCGTGCCCCAGCCC		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+52_48+53insGCCCCAGCCCCGT		intron_variant	Intron 1 of 15	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.48+52_48+53insGCCCCAGCCCCGT		intron_variant	Intron 1 of 14	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.48+52_48+53insGCCCCAGCCCCGT		intron_variant	Intron 1 of 14	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.48+52_48+53insGCCCCAGCCCCGT		intron_variant	Intron 1 of 14	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 119287 AN: 147756 Hom.: 47776 Cov.: 0

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.817

Gnomad MID AF: 0.822

Gnomad NFE AF: 0.874

Gnomad OTH AF: 0.821

GnomAD2 exomes AF: 0.811 AC: 95708 AN: 118050 AF XY: 0.815

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.823

Gnomad NFE exome AF: 0.870

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.851 AC: 1023448 AN: 1203070 Hom.: 442857 AF XY: 0.849 AC XY: 511399 AN XY: 602006

African (AFR) AF: 0.623 AC: 15656 AN: 25114

American (AMR) AF: 0.747 AC: 26226 AN: 35126

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 21633 AN: 23804

East Asian (EAS) AF: 0.761 AC: 26314 AN: 34588

South Asian (SAS) AF: 0.772 AC: 58160 AN: 75346

European-Finnish (FIN) AF: 0.827 AC: 28315 AN: 34244

Middle Eastern (MID) AF: 0.813 AC: 3052 AN: 3752

European-Non Finnish (NFE) AF: 0.871 AC: 800638 AN: 919484

Other (OTH) AF: 0.842 AC: 43454 AN: 51612

GnomAD4 genome AF: 0.807 AC: 119342 AN: 147850 Hom.: 47790 Cov.: 0 AF XY: 0.804 AC XY: 58119 AN XY: 72316

African (AFR) AF: 0.687 AC: 26072 AN: 37940

American (AMR) AF: 0.792 AC: 11957 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3154 AN: 3452

East Asian (EAS) AF: 0.770 AC: 3920 AN: 5090

South Asian (SAS) AF: 0.782 AC: 3759 AN: 4808

European-Finnish (FIN) AF: 0.817 AC: 8602 AN: 10524

Middle Eastern (MID) AF: 0.815 AC: 238 AN: 292

European-Non Finnish (NFE) AF: 0.873 AC: 59113 AN: 67674

Other (OTH) AF: 0.819 AC: 1693 AN: 2068

Alfa AF: 0.804 Hom.: 4921

Asia WGS AF: 0.775 AC: 2696 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: BA1 -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs45625236; hg19: chr16-68771418; COSMIC: COSV99931354;