chr16-68799040-C-T

Variant names:

• chr16-68799040-C-T
• rs1862748
• NM_004360.5:c.164-2630C>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.164-2630C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,150 control chromosomes in the GnomAD database, including 5,596 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 0.26 (5596 hom., cov: 32)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 27 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.164-2630C>T		intron	N/A	NP_004351.1
	CDH1	NM_001317184.2		c.164-2630C>T		intron	N/A	NP_001304113.1
	CDH1	NM_001317185.2		c.-1452-2630C>T		intron	N/A	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.164-2630C>T		intron	N/A	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.164-2630C>T		intron	N/A	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.235-2630C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39853 AN: 152032 Hom.: 5593 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.262 AC: 39873 AN: 152150 Hom.: 5596 Cov.: 32 AF XY: 0.260 AC XY: 19358 AN XY: 74374

African (AFR) AF: 0.174 AC: 7213 AN: 41508

American (AMR) AF: 0.318 AC: 4862 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1409 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1138 AN: 5164

South Asian (SAS) AF: 0.231 AC: 1113 AN: 4828

European-Finnish (FIN) AF: 0.233 AC: 2467 AN: 10576

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20663 AN: 68004

Other (OTH) AF: 0.286 AC: 603 AN: 2112

Alfa AF: 0.285 Hom.: 7141

Bravo AF: 0.263

Asia WGS AF: 0.254 AC: 885 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.75
DANN	Benign	0.25
PhyloP100		-1.1
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: rs1862748; hg19: chr16-68832943;