16-68757767-CTCCTTCCTTCCT-CTCCTTCCT

Variant names:

• chr16-68757767-CTCCT-C
• rs58548890
• NM_004360.5:c.163+19378_163+19381delCCTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004360.5(CDH1):​c.163+19378_163+19381delCCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (5979 hom., cov: 0)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460
• 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

ENSG00000309644 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.163+19378_163+19381delCCTT		intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.163+19378_163+19381delCCTT		intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1453+19378_-1453+19381delCCTT		intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1657+19378_-1657+19381delCCTT		intron_variant	Intron 2 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.163+19357_163+19360delTCCT		intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.282 AC: 41693 AN: 147728 Hom.: 5974 Cov.: 0

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.282 AC: 41730 AN: 147844 Hom.: 5979 Cov.: 0 AF XY: 0.280 AC XY: 20088 AN XY: 71798

African (AFR) AF: 0.296 AC: 11881 AN: 40148

American (AMR) AF: 0.295 AC: 4306 AN: 14592

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1341 AN: 3450

East Asian (EAS) AF: 0.278 AC: 1385 AN: 4988

South Asian (SAS) AF: 0.221 AC: 1023 AN: 4628

European-Finnish (FIN) AF: 0.221 AC: 2154 AN: 9736

Middle Eastern (MID) AF: 0.238 AC: 69 AN: 290

European-Non Finnish (NFE) AF: 0.279 AC: 18742 AN: 67070

Other (OTH) AF: 0.285 AC: 582 AN: 2040

Alfa AF: 0.0869 Hom.: 131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs58548890; hg19: chr16-68791670;