dbSNP rs2274239: CDH3:p.Lys652Lys (chr16-68691880-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001793.6(CDH3):c.1956G>A(p.Lys652Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,613,532 control chromosomes in the GnomAD database, including 293,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 28212 hom., cov: 31)

Exomes 𝑓: 0.60 ( 265543 hom. )

Consequence

CDH3
NM_001793.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.636

Publications

29 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 16-68691880-G-A is Benign according to our data. Variant chr16-68691880-G-A is described in ClinVar as Benign. ClinVar VariationId is 320250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.636 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 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.1956G>A	p.Lys652Lys	synonymous	Exon 13 of 16	NP_001784.2
CDH3	NM_001317195.3		c.1956G>A	p.Lys652Lys	synonymous	Exon 13 of 16	NP_001304124.1	P22223-2
CDH3	NM_001317196.2		c.1791G>A	p.Lys597Lys	synonymous	Exon 12 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.1956G>A	p.Lys652Lys	synonymous	Exon 13 of 16	ENSP00000264012.4	P22223-1
CDH3	ENST00000429102.6	TSL:1	c.1956G>A	p.Lys652Lys	synonymous	Exon 13 of 16	ENSP00000398485.2	P22223-2
CDH3	ENST00000914963.1		c.1986G>A	p.Lys662Lys	synonymous	Exon 13 of 16	ENSP00000585022.1

Frequencies

GnomAD3 genomes

AF:

0.607

AC:

92124

AN:

151838

Hom.:

28195

Cov.:

show subpopulations

Gnomad AFR

AF:

0.644

Gnomad AMI

AF:

0.690

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.565

Gnomad EAS

AF:

0.501

Gnomad SAS

AF:

0.550

Gnomad FIN

AF:

0.605

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.615

Gnomad OTH

AF:

0.603

GnomAD2 exomes

AF:

0.573

AC:

143927

AN:

251218

AF XY:

0.576

show subpopulations

Gnomad AFR exome

AF:

0.647

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.484

Gnomad FIN exome

AF:

0.601

Gnomad NFE exome

AF:

0.609

Gnomad OTH exome

AF:

0.578

GnomAD4 exome

AF:

0.601

AC:

878856

AN:

1461576

Hom.:

265543

Cov.:

AF XY:

0.600

AC XY:

436122

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.639

AC:

21377

AN:

33470

American (AMR)

AF:

0.479

AC:

21401

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.573

AC:

14983

AN:

26136

East Asian (EAS)

AF:

0.553

AC:

21935

AN:

39684

South Asian (SAS)

AF:

0.552

AC:

47573

AN:

86244

European-Finnish (FIN)

AF:

0.609

AC:

32526

AN:

53402

Middle Eastern (MID)

AF:

0.543

AC:

3084

AN:

5680

European-Non Finnish (NFE)

AF:

0.612

AC:

680166

AN:

1111864

Other (OTH)

AF:

0.593

AC:

35811

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

19585

39170

58755

78340

97925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18328

36656

54984

73312

91640

<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:

0.607

AC:

92192

AN:

151956

Hom.:

28212

Cov.:

AF XY:

0.602

AC XY:

44702

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.644

AC:

26688

AN:

41468

American (AMR)

AF:

0.530

AC:

8088

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.565

AC:

1958

AN:

3466

East Asian (EAS)

AF:

0.500

AC:

2582

AN:

5160

South Asian (SAS)

AF:

0.550

AC:

2643

AN:

4804

European-Finnish (FIN)

AF:

0.605

AC:

6386

AN:

10556

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.615

AC:

41767

AN:

67932

Other (OTH)

AF:

0.603

AC:

1265

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1799

3598

5396

7195

8994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

770

1540

2310

3080

3850

<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:

0.609

Hom.:

23488

Bravo

AF:

0.602

Asia WGS

AF:

0.497

AC:

1733

AN:

3478

EpiCase

AF:

0.607

EpiControl

AF:

0.606

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

EEM syndrome (2)

Congenital hypotrichosis with juvenile macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.3

(source)

DANN

Benign

0.35

PhyloP100

0.64

PromoterAI

0.011

Neutral

(source)

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over