rs2296409

Variant names:

• chr16-68679827-G-A
• rs2296409
• NM_001793.6:c.720G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001793.6(CDH3):​c.720G>A​(p.Thr240Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,610,936 control chromosomes in the GnomAD database, including 307,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (29939 hom., cov: 30)
  • Exomes 𝑓: 0.61 (277357 hom.)
• Consequence: CDH3 NM_001793.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.96
• Publications: 32 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-68679827-G-A is Benign according to our data. Variant chr16-68679827-G-A is described in ClinVar as Benign. ClinVar VariationId is 320229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH3	NM_001793.6	c.720G>A	p.Thr240Thr	synonymous_variant	Exon 7 of 16	ENST00000264012.9	NP_001784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9	c.720G>A	p.Thr240Thr	synonymous_variant	Exon 7 of 16	1	NM_001793.6	ENSP00000264012.4

Frequencies

GnomAD3 genomes AF: 0.627 AC: 94977 AN: 151494 Hom.: 29909 Cov.: 30

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.618

GnomAD2 exomes AF: 0.589 AC: 148094 AN: 251386 AF XY: 0.590

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.579

Gnomad EAS exome AF: 0.609

Gnomad FIN exome AF: 0.604

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.615 AC: 897082 AN: 1459324 Hom.: 277357 Cov.: 39 AF XY: 0.612 AC XY: 444731 AN XY: 726122

African (AFR) AF: 0.669 AC: 22380 AN: 33450

American (AMR) AF: 0.484 AC: 21646 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 15149 AN: 26120

East Asian (EAS) AF: 0.633 AC: 25102 AN: 39670

South Asian (SAS) AF: 0.542 AC: 46741 AN: 86208

European-Finnish (FIN) AF: 0.612 AC: 32649 AN: 53384

Middle Eastern (MID) AF: 0.552 AC: 3182 AN: 5760

European-Non Finnish (NFE) AF: 0.625 AC: 693317 AN: 1109694

Other (OTH) AF: 0.612 AC: 36916 AN: 60324

GnomAD4 genome AF: 0.627 AC: 95063 AN: 151612 Hom.: 29939 Cov.: 30 AF XY: 0.622 AC XY: 46080 AN XY: 74064

African (AFR) AF: 0.674 AC: 27848 AN: 41318

American (AMR) AF: 0.543 AC: 8266 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1983 AN: 3466

East Asian (EAS) AF: 0.627 AC: 3220 AN: 5132

South Asian (SAS) AF: 0.546 AC: 2610 AN: 4784

European-Finnish (FIN) AF: 0.610 AC: 6400 AN: 10490

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42594 AN: 67898

Other (OTH) AF: 0.619 AC: 1300 AN: 2100

Alfa AF: 0.618 Hom.: 52245

Bravo AF: 0.624

Asia WGS AF: 0.554 AC: 1929 AN: 3476

EpiCase AF: 0.621

EpiControl AF: 0.618

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

EEM syndrome Benign:2

Jan 12, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital hypotrichosis with juvenile macular dystrophy Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.28
DANN	Benign	0.43
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2296409; hg19: chr16-68713730; COSMIC: COSV50558303; COSMIC: COSV50558303;