Genetic Variant NM_001793.6:c.612C>A (chr16-68678827-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001793.6(CDH3):c.612C>A(p.Ile204Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,738 control chromosomes in the GnomAD database, including 17,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2695 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14714 hom. )

Consequence

CDH3
NM_001793.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -8.82

Publications

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

CDH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 16-68678827-C-A is Benign according to our data. Variant chr16-68678827-C-A is described in ClinVar as Benign. ClinVar VariationId is 320227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001793.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH3	NM_001793.6	MANE Select	c.612C>A	p.Ile204Ile	synonymous	Exon 6 of 16	NP_001784.2
CDH3	NM_001317195.3		c.612C>A	p.Ile204Ile	synonymous	Exon 6 of 16	NP_001304124.1	P22223-2
CDH3	NM_001317196.2		c.447C>A	p.Ile149Ile	synonymous	Exon 5 of 15	NP_001304125.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH3	ENST00000264012.9	TSL:1 MANE Select	c.612C>A	p.Ile204Ile	synonymous	Exon 6 of 16	ENSP00000264012.4	P22223-1
CDH3	ENST00000429102.6	TSL:1	c.612C>A	p.Ile204Ile	synonymous	Exon 6 of 16	ENSP00000398485.2	P22223-2
CDH3	ENST00000914963.1		c.612C>A	p.Ile204Ile	synonymous	Exon 6 of 16	ENSP00000585022.1

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26292

AN:

151992

Hom.:

2694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0774

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.168

GnomAD2 exomes

AF:

0.126

AC:

31744

AN:

251260

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.294

Gnomad AMR exome

AF:

0.0730

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.176

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.135

AC:

197528

AN:

1461628

Hom.:

14714

Cov.:

AF XY:

0.133

AC XY:

96961

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.296

AC:

9903

AN:

33474

American (AMR)

AF:

0.0780

AC:

3490

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2981

AN:

26132

East Asian (EAS)

AF:

0.000554

AC:

AN:

39680

South Asian (SAS)

AF:

0.0757

AC:

6529

AN:

86258

European-Finnish (FIN)

AF:

0.173

AC:

9234

AN:

53370

Middle Eastern (MID)

AF:

0.124

AC:

716

AN:

5768

European-Non Finnish (NFE)

AF:

0.141

AC:

156542

AN:

1111840

Other (OTH)

AF:

0.134

AC:

8111

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

9659

19317

28976

38634

48293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5518

11036

16554

22072

27590

<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:

0.173

AC:

26328

AN:

152110

Hom.:

2695

Cov.:

AF XY:

0.169

AC XY:

12594

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.287

AC:

11921

AN:

41468

American (AMR)

AF:

0.104

AC:

1586

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

404

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5170

South Asian (SAS)

AF:

0.0774

AC:

373

AN:

4818

European-Finnish (FIN)

AF:

0.165

AC:

1752

AN:

10598

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.143

AC:

9730

AN:

67978

Other (OTH)

AF:

0.168

AC:

353

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1095

2191

3286

4382

5477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.144

Hom.:

4066

Bravo

AF:

0.174

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

EpiCase

AF:

0.143

EpiControl

AF:

0.143

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

EEM syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

2.6

(source)

DANN

Benign

0.70

PhyloP100

-8.8

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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