chr16-68833553-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.*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:10

Conservation

PhyloP100: -1.45

Publications

35 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:

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.*54C>T	3_prime_UTR	Exon 16 of 16	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317184.2		c.*54C>T	3_prime_UTR	Exon 15 of 15	NP_001304113.1	P12830-2
CDH1	NM_001317185.2		c.*54C>T	3_prime_UTR	Exon 16 of 16	NP_001304114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.*54C>T	3_prime_UTR	Exon 16 of 16	ENSP00000261769.4	P12830-1
CDH1	ENST00000566612.5	TSL:1	n.*943C>T	non_coding_transcript_exon	Exon 15 of 15	ENSP00000454782.1	H3BNC6
CDH1	ENST00000566612.5	TSL:1	n.*943C>T	3_prime_UTR	Exon 15 of 15	ENSP00000454782.1	H3BNC6

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

African (AFR)

AF:

0.201

AC:

6060

AN:

30168

American (AMR)

AF:

0.181

AC:

8052

AN:

44404

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

3542

AN:

25082

East Asian (EAS)

AF:

0.143

AC:

5575

AN:

38910

South Asian (SAS)

AF:

0.0944

AC:

7816

AN:

82770

European-Finnish (FIN)

AF:

0.176

AC:

9228

AN:

52518

Middle Eastern (MID)

AF:

0.176

AC:

696

AN:

3948

European-Non Finnish (NFE)

AF:

0.153

AC:

146858

AN:

962724

Other (OTH)

AF:

0.156

AC:

8563

AN:

54900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

9009

18018

27026

36035

45044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4934

9868

14802

19736

24670

<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:

0.167

AC:

25417

AN:

151972

Hom.:

2099

Cov.:

AF XY:

0.166

AC XY:

12333

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.195

AC:

8086

AN:

41464

American (AMR)

AF:

0.172

AC:

2616

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

520

AN:

3468

East Asian (EAS)

AF:

0.156

AC:

804

AN:

5166

South Asian (SAS)

AF:

0.0956

AC:

460

AN:

4810

European-Finnish (FIN)

AF:

0.168

AC:

1775

AN:

10552

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.156

AC:

10634

AN:

67958

Other (OTH)

AF:

0.163

AC:

344

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1056

2112

3168

4224

5280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.101

Hom.:

235

Bravo

AF:

0.173

Asia WGS

AF:

0.147

AC:

508

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary diffuse gastric adenocarcinoma (3)

not provided (3)

not specified (2)

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

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.5

(source)

DANN

Benign

0.77

PhyloP100

-1.4

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

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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