NM_004360.5:c.2076T>C

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.2076T>C (p.Ala692=) variant has an allele frequency of 0.88894 (88.89%, 22156/24924 alleles, 9856 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2_Supporting). 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_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA169363/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.70 ( 38079 hom., cov: 30)

Exomes 𝑓: 0.64 ( 297080 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:24

Conservation

PhyloP100: 0.0880

Publications

81 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	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	NM_004360.5	MANE Select	c.2076T>C	p.Ala692Ala	synonymous	Exon 13 of 16	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317184.2		c.1893T>C	p.Ala631Ala	synonymous	Exon 12 of 15	NP_001304113.1	P12830-2
CDH1	NM_001317185.2		c.528T>C	p.Ala176Ala	synonymous	Exon 13 of 16	NP_001304114.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH1	ENST00000261769.10	TSL:1 MANE Select	c.2076T>C	p.Ala692Ala	synonymous	Exon 13 of 16	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.1893T>C	p.Ala631Ala	synonymous	Exon 12 of 15	ENSP00000414946.2	P12830-2
CDH1	ENST00000562836.5	TSL:1	n.2147T>C		non_coding_transcript_exon	Exon 12 of 15

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106055

AN:

151870

Hom.:

38020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.884

Gnomad AMI

AF:

0.595

Gnomad AMR

AF:

0.653

Gnomad ASJ

AF:

0.632

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.573

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.628

Gnomad OTH

AF:

0.681

GnomAD2 exomes

AF:

0.651

AC:

163615

AN:

251308

AF XY:

0.645

show subpopulations

Gnomad AFR exome

AF:

0.891

Gnomad AMR exome

AF:

0.666

Gnomad ASJ exome

AF:

0.631

Gnomad EAS exome

AF:

0.650

Gnomad FIN exome

AF:

0.592

Gnomad NFE exome

AF:

0.625

Gnomad OTH exome

AF:

0.641

GnomAD4 exome

AF:

0.635

AC:

928592

AN:

1461334

Hom.:

297080

Cov.:

AF XY:

0.634

AC XY:

461109

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.895

AC:

29966

AN:

33470

American (AMR)

AF:

0.660

AC:

29540

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

16251

AN:

26134

East Asian (EAS)

AF:

0.607

AC:

24082

AN:

39682

South Asian (SAS)

AF:

0.649

AC:

55966

AN:

86248

European-Finnish (FIN)

AF:

0.596

AC:

31771

AN:

53334

Middle Eastern (MID)

AF:

0.635

AC:

3656

AN:

5756

European-Non Finnish (NFE)

AF:

0.628

AC:

698025

AN:

1111602

Other (OTH)

AF:

0.651

AC:

39335

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

17726

35453

53179

70906

88632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18706

37412

56118

74824

93530

<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:

0.699

AC:

106179

AN:

151988

Hom.:

38079

Cov.:

AF XY:

0.696

AC XY:

51668

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.884

AC:

36669

AN:

41470

American (AMR)

AF:

0.653

AC:

9958

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.632

AC:

2193

AN:

3470

East Asian (EAS)

AF:

0.636

AC:

3282

AN:

5160

South Asian (SAS)

AF:

0.657

AC:

3153

AN:

4802

European-Finnish (FIN)

AF:

0.573

AC:

6039

AN:

10548

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.628

AC:

42703

AN:

67972

Other (OTH)

AF:

0.685

AC:

1447

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1557

3114

4672

6229

7786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<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:

0.645

Hom.:

59222

Bravo

AF:

0.711

Asia WGS

AF:

0.711

AC:

2471

AN:

3478

EpiCase

AF:

0.620

EpiControl

AF:

0.620

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

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

-0.88

CADD

Benign

6.3

(source)

DANN

Benign

0.45

PhyloP100

0.088

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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