16-68833553-C-T

Position:

chr16-68833553-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.*54C>T variant has an allele frequency of 0.18763 (18.76%, 1629/8682 alleles, 147 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel Variant Interpretation Guidelines Version 3.1): BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10647973/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.17 ( 2099 hom., cov: 32)

Exomes 𝑓: 0.15 ( 15571 hom. )

Consequence

CDH1
NM_004360.5 3_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: -1.45

Variant links:

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 links:

CDH1 (HGNC:):

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5 linkuse as main transcript	c.*54C>T	3_prime_UTR_variant	16/16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 linkuse as main transcript	c.*54C>T	3_prime_UTR_variant	15/15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 linkuse as main transcript	c.*54C>T	3_prime_UTR_variant	16/16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 linkuse as main transcript	c.*54C>T	3_prime_UTR_variant	15/15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.*54C>T		3_prime_UTR_variant	16/16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25367

AN:

151854

Hom.:

2090

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.172

Gnomad ASJ

AF:

0.150

Gnomad EAS

AF:

0.156

Gnomad SAS

AF:

0.0953

Gnomad FIN

AF:

0.168

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.158

GnomAD4 exome

AF:

0.152

AC:

196390

AN:

1295424

Hom.:

15571

Cov.:

AF XY:

0.149

AC XY:

97527

AN XY:

653218

show subpopulations

Gnomad4 AFR exome

AF:

0.201

Gnomad4 AMR exome

AF:

0.181

Gnomad4 ASJ exome

AF:

0.141

Gnomad4 EAS exome

AF:

0.143

Gnomad4 SAS exome

AF:

0.0944

Gnomad4 FIN exome

AF:

0.176

Gnomad4 NFE exome

AF:

0.153

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.167

AC:

25417

AN:

151972

Hom.:

2099

Cov.:

AF XY:

0.166

AC XY:

12333

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.195

Gnomad4 AMR

AF:

0.172

Gnomad4 ASJ

AF:

0.150

Gnomad4 EAS

AF:

0.156

Gnomad4 SAS

AF:

0.0956

Gnomad4 FIN

AF:

0.168

Gnomad4 NFE

AF:

0.156

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.101

Hom.:

235

Bravo

AF:

0.173

Asia WGS

AF:

0.147

AC:

508

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21459793, 19563064, 21432908) -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 10, 2023

The NM_004360.5(CDH1):c.*54C>T variant has an allele frequency of 0.18763 (18.76%, 1629/8682 alleles, 147 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel Variant Interpretation Guidelines Version 3.1): BA1, BP2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.5

DANN

Benign

0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over