chr16-68687630-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001793.6(CDH3):c.1689G>C(p.Gln563His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,374 control chromosomes in the GnomAD database, including 131,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q563Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 9276 hom., cov: 30)

Exomes 𝑓: 0.40 ( 122580 hom. )

Consequence

CDH3
NM_001793.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.134

Publications

40 publications found

Variant links:

Genes affected

CDH3 (HGNC:1762): (cadherin 3) 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. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. Mutations in this gene are associated with hypotrichosis with juvenile macular dystrophy and ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS). [provided by RefSeq, Nov 2015]

CDH3 Gene-Disease associations (from GenCC):

EEM syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital hypotrichosis with juvenile macular dystrophy
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

CDH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6865134E-4).

BP6

Variant 16-68687630-G-C is Benign according to our data. Variant chr16-68687630-G-C is described in ClinVar as Benign. ClinVar VariationId is 320245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH3	NM_001793.6 link	c.1689G>C	p.Gln563His	missense_variant	Exon 12 of 16	ENST00000264012.9	NP_001784.2	P22223-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9 link	c.1689G>C	p.Gln563His	missense_variant	Exon 12 of 16	1	NM_001793.6	ENSP00000264012.4		P22223-1

Frequencies

GnomAD3 genomes

AF:

0.316

AC:

48025

AN:

151882

Hom.:

9275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0843

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.350

Gnomad ASJ

AF:

0.357

Gnomad EAS

AF:

0.511

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.373

AC:

93768

AN:

251448

AF XY:

0.378

show subpopulations

Gnomad AFR exome

AF:

0.0786

Gnomad AMR exome

AF:

0.345

Gnomad ASJ exome

AF:

0.370

Gnomad EAS exome

AF:

0.491

Gnomad FIN exome

AF:

0.397

Gnomad NFE exome

AF:

0.408

Gnomad OTH exome

AF:

0.372

GnomAD4 exome

AF:

0.404

AC:

590537

AN:

1461374

Hom.:

122580

Cov.:

AF XY:

0.403

AC XY:

292789

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.0691

AC:

2312

AN:

33476

American (AMR)

AF:

0.350

AC:

15634

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

9665

AN:

26134

East Asian (EAS)

AF:

0.543

AC:

21530

AN:

39678

South Asian (SAS)

AF:

0.344

AC:

29713

AN:

86254

European-Finnish (FIN)

AF:

0.407

AC:

21726

AN:

53404

Middle Eastern (MID)

AF:

0.279

AC:

1607

AN:

5768

European-Non Finnish (NFE)

AF:

0.418

AC:

465180

AN:

1111552

Other (OTH)

AF:

0.384

AC:

23170

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

20764

41529

62293

83058

103822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14170

28340

42510

56680

70850

<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:

0.316

AC:

48030

AN:

152000

Hom.:

9276

Cov.:

AF XY:

0.317

AC XY:

23562

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.0841

AC:

3489

AN:

41502

American (AMR)

AF:

0.350

AC:

5354

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

1238

AN:

3472

East Asian (EAS)

AF:

0.510

AC:

2613

AN:

5122

South Asian (SAS)

AF:

0.338

AC:

1625

AN:

4804

European-Finnish (FIN)

AF:

0.413

AC:

4368

AN:

10566

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.415

AC:

28206

AN:

67942

Other (OTH)

AF:

0.317

AC:

667

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1574

3148

4722

6296

7870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.387

Hom.:

8835

Bravo

AF:

0.303

TwinsUK

AF:

0.411

AC:

1523

ALSPAC

AF:

0.429

AC:

1654

ESP6500AA

AF:

0.0901

AC:

396

ESP6500EA

AF:

0.417

AC:

3590

ExAC

AF:

0.366

AC:

44402

Asia WGS

AF:

0.350

AC:

1218

AN:

3478

EpiCase

AF:

0.406

EpiControl

AF:

0.398

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EEM syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.5

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.00017

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;L

PhyloP100

-0.13

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.062

Sift

Benign

0.33

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.029

B;.

Vest4

0.30

MutPred

0.24

Gain of catalytic residue at L565 (P = 0.0792);Gain of catalytic residue at L565 (P = 0.0792);

MPC

0.76

ClinPred

0.0029

GERP RS

-3.3

Varity_R

0.064

gMVP

0.75

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over