rs28372783

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004360.5(CDH1):c.-197A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 574,956 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 89 hom., cov: 33)

Exomes 𝑓: 0.012 ( 216 hom. )

Consequence

CDH1
NM_004360.5 upstream_gene

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.06

Publications

9 publications found

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 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

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 16-68737219-A-C is Benign according to our data. Variant chr16-68737219-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 676637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CDH1	NM_004360.5 link	c.-197A>C	upstream_gene_variant	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 link	c.-197A>C	upstream_gene_variant		NP_001304113.1
CDH1	NM_001317185.2 link	c.-1812A>C	upstream_gene_variant		NP_001304114.1
CDH1	NM_001317186.2 link	c.-2016A>C	upstream_gene_variant		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein
CDH1	ENST00000261769.10 link	c.-197A>C	upstream_gene_variant	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6 link	c.-197A>C	upstream_gene_variant	1		ENSP00000414946.2
CDH1	ENST00000566612.5 link	n.-197A>C	upstream_gene_variant	1		ENSP00000454782.1
CDH1	ENST00000566510.5 link	n.-197A>C	upstream_gene_variant	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1657

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0461

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.00833

Gnomad FIN

AF:

0.00265

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000707

Gnomad OTH

AF:

0.0148

GnomAD4 exome

AF:

0.0120

AC:

5063

AN:

423036

Hom.:

216

Cov.:

AF XY:

0.0111

AC XY:

2480

AN XY:

222822

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

8804

American (AMR)

AF:

0.0708

AC:

1156

AN:

16326

Ashkenazi Jewish (ASJ)

AF:

0.00450

AC:

AN:

12664

East Asian (EAS)

AF:

0.110

AC:

3016

AN:

27352

South Asian (SAS)

AF:

0.00652

AC:

278

AN:

42656

European-Finnish (FIN)

AF:

0.00256

AC:

AN:

29328

Middle Eastern (MID)

AF:

0.00265

AC:

AN:

1888

European-Non Finnish (NFE)

AF:

0.000683

AC:

177

AN:

259166

Other (OTH)

AF:

0.0112

AC:

279

AN:

24852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

246

492

738

984

1230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0109

AC:

1657

AN:

151920

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

878

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00292

AC:

121

AN:

41428

American (AMR)

AF:

0.0464

AC:

708

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3464

East Asian (EAS)

AF:

0.131

AC:

672

AN:

5142

South Asian (SAS)

AF:

0.00834

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00265

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000707

AC:

AN:

67930

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.0166

Asia WGS

AF:

0.0680

AC:

236

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 17, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.3

(source)

DANN

Benign

0.79

PhyloP100

-1.1

PromoterAI

0.30

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over