rs2274239

chr16-68691880-G-Achr16-68691880-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001793.6(CDH3):c.1956G>A(p.Lys652=) 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:5
• Conservation: PhyloP100: 0.636

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]

ACMG classification

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	UniProt
CDH3	NM_001793.6	c.1956G>A	p.Lys652=	synonymous_variant	13/16	ENST00000264012.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH3	ENST00000264012.9	c.1956G>A	p.Lys652=	synonymous_variant	13/16	1	NM_001793.6	P1

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

GnomAD3 exomes AF: 0.573 AC: 143927 AN: 251218 Hom.: 41694 AF XY: 0.576 AC XY: 78216 AN XY: 135826

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

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.: 31 AF XY: 0.602 AC XY: 44702 AN XY: 74270

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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. -

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

Other links and lift over

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