rs2274239

Variant names:

• chr16-68691880-G-A
• rs2274239
• NM_001793.6:c.1956G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68691880-G-A
• chr16-68691880-G-C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.636
• Publications: 29 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=-0.58).
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH3	NM_001793.6	c.1956G>A	p.Lys652Lys	synonymous_variant	Exon 13 of 16	ENST00000264012.9	NP_001784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9	c.1956G>A	p.Lys652Lys	synonymous_variant	Exon 13 of 16	1	NM_001793.6	ENSP00000264012.4

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92124 AN: 151838 Hom.: 28195 Cov.: 31

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

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.: 53 AF XY: 0.600 AC XY: 436122 AN XY: 727088

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

GnomAD4 genome AF: 0.607 AC: 92192 AN: 151956 Hom.: 28212 Cov.: 31 AF XY: 0.602 AC XY: 44702 AN XY: 74270

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

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

Significance: Benign

Submissions summary: Benign:6

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

- -

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

EEM syndrome Benign:2

Jan 13, 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	-0.58
CADD	Benign	4.3
DANN	Benign	0.35
PhyloP100		0.64
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2274239; hg19: chr16-68725783; COSMIC: COSV50555466; COSMIC: COSV50555466;