rs34939176

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.2164+17dup variant has an allele frequency of 0.1034 (10%, 3634/35146 alleles, 197 homozygotes) in the Latino 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/CA8130206/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.031 ( 120 hom., cov: 31)

Exomes 𝑓: 0.039 ( 1300 hom. )

Consequence

CDH1
NM_004360.5 intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:12

Conservation

PhyloP100: -0.266

Publications

8 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
CDH1-related diffuse gastric and lobular breast cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary diffuse gastric adenocarcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

CDH1 links:

ENSG00000260798 (HGNC:):

ENSG00000260798 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDH1	NM_004360.5	MANE Select	c.2164+17dupA	intron	N/A	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317184.2		c.1981+17dupA	intron	N/A	NP_001304113.1	P12830-2
CDH1	NM_001317185.2		c.616+17dupA	intron	N/A	NP_001304114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.2164+15_2164+16insA	intron	N/A	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.1981+15_1981+16insA	intron	N/A	ENSP00000414946.2	P12830-2
CDH1	ENST00000562836.5	TSL:1	n.2235+15_2235+16insA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4720

AN:

152110

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0710

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.0749

Gnomad SAS

AF:

0.0581

Gnomad FIN

AF:

0.0202

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0336

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0478

AC:

11608

AN:

243006

AF XY:

0.0465

show subpopulations

Gnomad AFR exome

AF:

0.00805

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.0786

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0320

Gnomad OTH exome

AF:

0.0430

GnomAD4 exome

AF:

0.0387

AC:

53830

AN:

1391720

Hom.:

1300

Cov.:

AF XY:

0.0391

AC XY:

27213

AN XY:

696346

show subpopulations

African (AFR)

AF:

0.00614

AC:

197

AN:

32062

American (AMR)

AF:

0.0979

AC:

4362

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

683

AN:

25740

East Asian (EAS)

AF:

0.0753

AC:

2962

AN:

39350

South Asian (SAS)

AF:

0.0608

AC:

5162

AN:

84868

European-Finnish (FIN)

AF:

0.0246

AC:

1174

AN:

47770

Middle Eastern (MID)

AF:

0.0244

AC:

138

AN:

5652

European-Non Finnish (NFE)

AF:

0.0351

AC:

36975

AN:

1053518

Other (OTH)

AF:

0.0374

AC:

2177

AN:

58196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

2548

5096

7644

10192

12740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1492

2984

4476

5968

7460

<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:

0.0311

AC:

4731

AN:

152228

Hom.:

120

Cov.:

AF XY:

0.0317

AC XY:

2360

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00669

AC:

278

AN:

41546

American (AMR)

AF:

0.0710

AC:

1085

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0309

AC:

107

AN:

3468

East Asian (EAS)

AF:

0.0741

AC:

384

AN:

5182

South Asian (SAS)

AF:

0.0580

AC:

279

AN:

4814

European-Finnish (FIN)

AF:

0.0202

AC:

214

AN:

10596

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0336

AC:

2287

AN:

68010

Other (OTH)

AF:

0.0393

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

231

461

692

922

1153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0312

Hom.:

Bravo

AF:

0.0342

Asia WGS

AF:

0.0850

AC:

296

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Hereditary diffuse gastric adenocarcinoma (2)

Breast and/or ovarian cancer (1)

CDH1-related diffuse gastric and lobular breast cancer syndrome (1)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over