chr16-68737515-C-CGCCCCAGCCCCGT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004360.5(CDH1):c.48+62_48+63insCGTGCCCCAGCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 1,350,920 control chromosomes in the GnomAD database, including 490,647 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 47790 hom., cov: 0)

Exomes 𝑓: 0.85 ( 442857 hom. )

Consequence

CDH1
NM_004360.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.554

Publications

1 publications found

Variant links:

COSMIC-nc: COSV99931354

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 -16 ACMG points.

BP6

Variant 16-68737515-C-CGCCCCAGCCCCGT is Benign according to our data. Variant chr16-68737515-C-CGCCCCAGCCCCGT is described in ClinVar as Benign. ClinVar VariationId is 1243608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

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+62_48+63insCGTGCCCCAGCCC	intron	N/A	NP_004351.1	A0A0U2ZQU7
CDH1	NM_001317184.2		c.48+62_48+63insCGTGCCCCAGCCC	intron	N/A	NP_001304113.1	P12830-2
CDH1	NM_001317185.2		c.-1568+62_-1568+63insCGTGCCCCAGCCC	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+52_48+53insGCCCCAGCCCCGT	intron	N/A	ENSP00000261769.4	P12830-1
CDH1	ENST00000422392.6	TSL:1	c.48+52_48+53insGCCCCAGCCCCGT	intron	N/A	ENSP00000414946.2	P12830-2
CDH1	ENST00000566612.5	TSL:1	n.48+52_48+53insGCCCCAGCCCCGT	intron	N/A	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes

AF:

0.807

AC:

119287

AN:

147756

Hom.:

47776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.687

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.792

Gnomad ASJ

AF:

0.914

Gnomad EAS

AF:

0.770

Gnomad SAS

AF:

0.782

Gnomad FIN

AF:

0.817

Gnomad MID

AF:

0.822

Gnomad NFE

AF:

0.874

Gnomad OTH

AF:

0.821

GnomAD2 exomes

AF:

0.811

AC:

95708

AN:

118050

AF XY:

0.815

show subpopulations

Gnomad AFR exome

AF:

0.640

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.912

Gnomad EAS exome

AF:

0.760

Gnomad FIN exome

AF:

0.823

Gnomad NFE exome

AF:

0.870

Gnomad OTH exome

AF:

0.843

GnomAD4 exome

AF:

0.851

AC:

1023448

AN:

1203070

Hom.:

442857

AF XY:

0.849

AC XY:

511399

AN XY:

602006

show subpopulations

African (AFR)

AF:

0.623

AC:

15656

AN:

25114

American (AMR)

AF:

0.747

AC:

26226

AN:

35126

Ashkenazi Jewish (ASJ)

AF:

0.909

AC:

21633

AN:

23804

East Asian (EAS)

AF:

0.761

AC:

26314

AN:

34588

South Asian (SAS)

AF:

0.772

AC:

58160

AN:

75346

European-Finnish (FIN)

AF:

0.827

AC:

28315

AN:

34244

Middle Eastern (MID)

AF:

0.813

AC:

3052

AN:

3752

European-Non Finnish (NFE)

AF:

0.871

AC:

800638

AN:

919484

Other (OTH)

AF:

0.842

AC:

43454

AN:

51612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

6598

13196

19795

26393

32991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16482

32964

49446

65928

82410

<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:

0.807

AC:

119342

AN:

147850

Hom.:

47790

Cov.:

AF XY:

0.804

AC XY:

58119

AN XY:

72316

show subpopulations

African (AFR)

AF:

0.687

AC:

26072

AN:

37940

American (AMR)

AF:

0.792

AC:

11957

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

3154

AN:

3452

East Asian (EAS)

AF:

0.770

AC:

3920

AN:

5090

South Asian (SAS)

AF:

0.782

AC:

3759

AN:

4808

European-Finnish (FIN)

AF:

0.817

AC:

8602

AN:

10524

Middle Eastern (MID)

AF:

0.815

AC:

238

AN:

292

European-Non Finnish (NFE)

AF:

0.873

AC:

59113

AN:

67674

Other (OTH)

AF:

0.819

AC:

1693

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1213

2426

3640

4853

6066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.804

Hom.:

4921

Asia WGS

AF:

0.775

AC:

2696

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.55

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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