16-68822185-C-T

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.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 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/CA165821/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.020 ( 57 hom., cov: 31)

Exomes 𝑓: 0.0081 ( 165 hom. )

Consequence

CDH1
NM_001317186.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel B:20

Conservation

PhyloP100: -4.77

Publications

25 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_001317186.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	NM_004360.5	MANE Select	c.1896C>T	p.His632His	synonymous	Exon 12 of 16	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317186.2		c.-70C>T		5_prime_UTR_premature_start_codon_gain	Exon 11 of 15	NP_001304115.1
CDH1	NM_001317184.2		c.1713C>T	p.His571His	synonymous	Exon 11 of 15	NP_001304113.1	P12830-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1896C>T	p.His632His	synonymous	Exon 12 of 16	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.1713C>T	p.His571His	synonymous	Exon 11 of 15	ENSP00000414946.2	P12830-2
CDH1	ENST00000562836.5	TSL:1	n.1967C>T		non_coding_transcript_exon	Exon 11 of 15

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3008

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0486

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.0248

GnomAD2 exomes

AF:

0.0106

AC:

2670

AN:

251464

AF XY:

0.00978

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.00806

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.00810

AC:

11839

AN:

1461840

Hom.:

165

Cov.:

AF XY:

0.00801

AC XY:

5826

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0536

AC:

1795

AN:

33476

American (AMR)

AF:

0.0156

AC:

697

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00876

AC:

229

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00230

AC:

198

AN:

86256

European-Finnish (FIN)

AF:

0.00520

AC:

278

AN:

53416

Middle Eastern (MID)

AF:

0.0870

AC:

502

AN:

5768

European-Non Finnish (NFE)

AF:

0.00657

AC:

7308

AN:

1111968

Other (OTH)

AF:

0.0137

AC:

827

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

626

1251

1877

2502

3128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.0198

AC:

3022

AN:

152256

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1451

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0489

AC:

2032

AN:

41530

American (AMR)

AF:

0.0171

AC:

261

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00725

AC:

493

AN:

68012

Other (OTH)

AF:

0.0246

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

148

296

444

592

740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0125

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0117

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Hereditary diffuse gastric adenocarcinoma (5)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

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

Malignant tumor of breast (1)

Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.26

(source)

DANN

Benign

0.82

PhyloP100

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

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

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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