rs9935563

Variant names:

• chr16-68827753-T-C
• rs9935563
• NM_004360.5:c.2165-421T>C

Variant summary

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

The NM_004360.5(CDH1):​c.2165-421T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 151,696 control chromosomes in the GnomAD database, including 38,226 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 0.70 (38226 hom., cov: 29)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.309
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2165-421T>C		intron_variant	Intron 13 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1982-421T>C		intron_variant	Intron 12 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.617-421T>C		intron_variant	Intron 13 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.200-421T>C		intron_variant	Intron 12 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2165-421T>C		intron_variant	Intron 13 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106200 AN: 151576 Hom.: 38165 Cov.: 29

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.684

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

GnomAD4 genome AF: 0.701 AC: 106327 AN: 151696 Hom.: 38226 Cov.: 29 AF XY: 0.698 AC XY: 51718 AN XY: 74048

African (AFR) AF: 0.885 AC: 36652 AN: 41418

American (AMR) AF: 0.656 AC: 9977 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2197 AN: 3470

East Asian (EAS) AF: 0.636 AC: 3257 AN: 5118

South Asian (SAS) AF: 0.673 AC: 3226 AN: 4790

European-Finnish (FIN) AF: 0.575 AC: 6017 AN: 10464

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42838 AN: 67920

Other (OTH) AF: 0.688 AC: 1449 AN: 2106

Alfa AF: 0.645 Hom.: 13746

Bravo AF: 0.712

Asia WGS AF: 0.714 AC: 2481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.90
DANN	Benign	0.62
PhyloP100		-0.31
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: rs9935563; hg19: chr16-68861656;