rs8049247

Variant names:

• chr16-68678827-C-A
• rs8049247
• NM_001793.6:c.612C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68678827-C-A
• chr16-68678827-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.82
• Publications: 24 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH3	NM_001793.6	c.612C>A	p.Ile204Ile	synonymous_variant	Exon 6 of 16	ENST00000264012.9	NP_001784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9	c.612C>A	p.Ile204Ile	synonymous_variant	Exon 6 of 16	1	NM_001793.6	ENSP00000264012.4

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26292 AN: 151992 Hom.: 2694 Cov.: 32

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

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.: 34 AF XY: 0.133 AC XY: 96961 AN XY: 727120

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: 22 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

GnomAD4 genome AF: 0.173 AC: 26328 AN: 152110 Hom.: 2695 Cov.: 32 AF XY: 0.169 AC XY: 12594 AN XY: 74390

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: 6 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: 53 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9730 AN: 67978

Other (OTH) AF: 0.168 AC: 353 AN: 2104

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EEM syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	2.6
DANN	Benign	0.70
PhyloP100		-8.8
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8049247; hg19: chr16-68712730; COSMIC: COSV50577794;