rs2274239

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 320250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68691880-G-A is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH3	NM_001793.6 linkuse as main transcript	c.1956G>A	p.Lys652Lys	synonymous_variant	13/16	ENST00000264012.9	NP_001784.2	P22223-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9 linkuse as main transcript	c.1956G>A	p.Lys652Lys	synonymous_variant	13/16	1	NM_001793.6	ENSP00000264012.4		P22223-1

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

GnomAD3 exomes

AF:

0.573

AC:

143927

AN:

251218

Hom.:

41694

AF XY:

0.576

AC XY:

78216

AN XY:

135826

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 SAS exome

AF:

0.554

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

Gnomad4 AFR exome

AF:

0.639

Gnomad4 AMR exome

AF:

0.479

Gnomad4 ASJ exome

AF:

0.573

Gnomad4 EAS exome

AF:

0.553

Gnomad4 SAS exome

AF:

0.552

Gnomad4 FIN exome

AF:

0.609

Gnomad4 NFE exome

AF:

0.612

Gnomad4 OTH exome

AF:

0.593

GnomAD4 genome

AF:

0.607

AC:

92192

AN:

151956

Hom.:

28212

Cov.:

AF XY:

0.602

AC XY:

44702

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.644

Gnomad4 AMR

AF:

0.530

Gnomad4 ASJ

AF:

0.565

Gnomad4 EAS

AF:

0.500

Gnomad4 SAS

AF:

0.550

Gnomad4 FIN

AF:

0.605

Gnomad4 NFE

AF:

0.615

Gnomad4 OTH

AF:

0.603

Alfa

AF:

0.610

Hom.:

17862

Bravo

AF:

0.602

Asia WGS

AF:

0.497

AC:

1733

AN:

3478

EpiCase

AF:

0.607

EpiControl

AF:

0.606

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

EEM syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Congenital hypotrichosis with juvenile macular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.3

DANN

Benign

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over