16-68744554-C-T

Variant names:

• chr16-68744554-C-T
• rs7200690
• NM_004360.5:c.163+6143C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004360.5(CDH1):​c.163+6143C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 151,986 control chromosomes in the GnomAD database, including 4,507 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4507 hom., cov: 31)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.300
• Publications: 13 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.163+6143C>T		intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.163+6143C>T		intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1453+6143C>T		intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1657+6143C>T		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+6143C>T		intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34610 AN: 151868 Hom.: 4510 Cov.: 31

Gnomad AFR AF: 0.0960

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.228 AC: 34605 AN: 151986 Hom.: 4507 Cov.: 31 AF XY: 0.228 AC XY: 16949 AN XY: 74270

African (AFR) AF: 0.0957 AC: 3970 AN: 41474

American (AMR) AF: 0.279 AC: 4249 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1370 AN: 3464

East Asian (EAS) AF: 0.278 AC: 1434 AN: 5164

South Asian (SAS) AF: 0.249 AC: 1198 AN: 4812

European-Finnish (FIN) AF: 0.237 AC: 2503 AN: 10566

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19043 AN: 67976

Other (OTH) AF: 0.246 AC: 517 AN: 2100

Alfa AF: 0.274 Hom.: 2525

Bravo AF: 0.225

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.58
PhyloP100		-0.30
Mutation Taster		=99/1	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: rs7200690; hg19: chr16-68778457;