chr16-68737515-C-CGCCCCAGCCCCAT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004360.5(CDH1):​c.48+62_48+63insCATGCCCCAGCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,203,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.554
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000332 AC: 4 AN: 1203556 Hom.: 0 AF XY: 0.00000332 AC XY: 2 AN XY: 602238

African (AFR) AF: 0.00 AC: 0 AN: 25162

American (AMR) AF: 0.00 AC: 0 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23806

East Asian (EAS) AF: 0.00 AC: 0 AN: 34602

South Asian (SAS) AF: 0.00 AC: 0 AN: 75374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3752

European-Non Finnish (NFE) AF: 0.00000435 AC: 4 AN: 919852

Other (OTH) AF: 0.00 AC: 0 AN: 51630

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.55

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;