rs3743674

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.48+6C>T variant has an allele frequency of 0.81161 (81%, 129,383/159,416 alleles) in the gnomAD cohort (BA1). 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA200462/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.80 ( 50036 hom., cov: 35)

Exomes 𝑓: 0.87 ( 522253 hom. )

Consequence

CDH1
NM_004360.5 splice_region, intron

Scores

Splicing: ADA: 0.00001643

Clinical Significance

Benign reviewed by expert panel U:1B:24

Conservation

PhyloP100: -0.132

Publications

48 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 -8 ACMG points.

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.48+6C>T	splice_region intron	N/A	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317184.2		c.48+6C>T	splice_region intron	N/A	NP_001304113.1	P12830-2
CDH1	NM_001317185.2		c.-1568+6C>T	splice_region 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.48+6C>T	splice_region intron	N/A	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.48+6C>T	splice_region intron	N/A	ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5	TSL:1	n.48+6C>T	splice_region intron	N/A	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes

AF:

0.805

AC:

122401

AN:

152054

Hom.:

50031

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.924

Gnomad AMR

AF:

0.799

Gnomad ASJ

AF:

0.930

Gnomad EAS

AF:

0.773

Gnomad SAS

AF:

0.784

Gnomad FIN

AF:

0.825

Gnomad MID

AF:

0.850

Gnomad NFE

AF:

0.884

Gnomad OTH

AF:

0.831

GnomAD2 exomes

AF:

0.816

AC:

108886

AN:

133422

AF XY:

0.820

show subpopulations

Gnomad AFR exome

AF:

0.647

Gnomad AMR exome

AF:

0.741

Gnomad ASJ exome

AF:

0.928

Gnomad EAS exome

AF:

0.765

Gnomad FIN exome

AF:

0.827

Gnomad NFE exome

AF:

0.878

Gnomad OTH exome

AF:

0.857

GnomAD4 exome

AF:

0.867

AC:

1200027

AN:

1384830

Hom.:

522253

Cov.:

AF XY:

0.865

AC XY:

591464

AN XY:

684018

show subpopulations

African (AFR)

AF:

0.652

AC:

20479

AN:

31398

American (AMR)

AF:

0.756

AC:

27499

AN:

36368

Ashkenazi Jewish (ASJ)

AF:

0.929

AC:

23342

AN:

25138

East Asian (EAS)

AF:

0.765

AC:

27424

AN:

35852

South Asian (SAS)

AF:

0.778

AC:

61563

AN:

79162

European-Finnish (FIN)

AF:

0.837

AC:

29015

AN:

34660

Middle Eastern (MID)

AF:

0.835

AC:

3440

AN:

4118

European-Non Finnish (NFE)

AF:

0.886

AC:

957646

AN:

1080310

Other (OTH)

AF:

0.858

AC:

49619

AN:

57824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

8095

16190

24286

32381

40476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20952

41904

62856

83808

104760

<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:

0.805

AC:

122443

AN:

152170

Hom.:

50036

Cov.:

AF XY:

0.800

AC XY:

59502

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.663

AC:

27507

AN:

41508

American (AMR)

AF:

0.799

AC:

12229

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.930

AC:

3228

AN:

3470

East Asian (EAS)

AF:

0.773

AC:

3989

AN:

5162

South Asian (SAS)

AF:

0.784

AC:

3782

AN:

4826

European-Finnish (FIN)

AF:

0.825

AC:

8740

AN:

10596

Middle Eastern (MID)

AF:

0.849

AC:

248

AN:

292

European-Non Finnish (NFE)

AF:

0.884

AC:

60127

AN:

67988

Other (OTH)

AF:

0.828

AC:

1750

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1183

2365

3548

4730

5913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<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:

0.849

Hom.:

10832

Bravo

AF:

0.796

Asia WGS

AF:

0.774

AC:

2692

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Hereditary diffuse gastric adenocarcinoma (5)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Prostate cancer (2)

Blepharocheilodontic syndrome 1 (1)

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

Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.2

(source)

DANN

Benign

0.92

PhyloP100

-0.13

PromoterAI

-0.063

Neutral

(source)

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000016

dbscSNV1_RF

Benign

0.032

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