rs7196661

Variant names:

• chr16-68740009-C-T
• rs7196661
• NM_004360.5:c.163+1598C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004360.5(CDH1):​c.163+1598C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 152,118 control chromosomes in the GnomAD database, including 50,112 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 0.81 (50112 hom., cov: 32)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.994
• Publications: 14 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.163+1598C>T		intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.163+1598C>T		intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1453+1598C>T		intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1657+1598C>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+1598C>T		intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.163+1598C>T		intron_variant	Intron 2 of 14	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.163+1598C>T		intron_variant	Intron 2 of 14	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.163+1598C>T		intron_variant	Intron 2 of 14	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.806 AC: 122488 AN: 152000 Hom.: 50106 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.930

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.886

Gnomad OTH AF: 0.830

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

GnomAD4 genome AF: 0.806 AC: 122532 AN: 152118 Hom.: 50112 Cov.: 32 AF XY: 0.801 AC XY: 59544 AN XY: 74366

African (AFR) AF: 0.663 AC: 27490 AN: 41456

American (AMR) AF: 0.799 AC: 12210 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 3230 AN: 3472

East Asian (EAS) AF: 0.771 AC: 3988 AN: 5172

South Asian (SAS) AF: 0.784 AC: 3775 AN: 4814

European-Finnish (FIN) AF: 0.826 AC: 8746 AN: 10594

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.886 AC: 60255 AN: 68018

Other (OTH) AF: 0.827 AC: 1746 AN: 2112

Alfa AF: 0.827 Hom.: 9171

Bravo AF: 0.797

Asia WGS AF: 0.774 AC: 2692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		0.99
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: rs7196661; hg19: chr16-68773912;