rs2296408

chr16-68679920-C-Achr16-68679920-C-Gchr16-68679920-C-T

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.813C>A(p.Thr271=) 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 1,613,428 control chromosomes in the GnomAD database, including 307,510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (29975 hom., cov: 31)
  • Exomes 𝑓: 0.61 (277535 hom.)
• Consequence: CDH3 NM_001793.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.67

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=-0.72).
• BP6: Variant 16-68679920-C-A is Benign according to our data. Variant chr16-68679920-C-A is described in ClinVar as [Benign]. Clinvar id is 320230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 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/exons	MANE	UniProt
CDH3	NM_001793.6	c.813C>A	p.Thr271=	synonymous_variant	7/16	ENST00000264012.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH3	ENST00000264012.9	c.813C>A	p.Thr271=	synonymous_variant	7/16	1	NM_001793.6	P1
CDH3	ENST00000429102.6	c.813C>A	p.Thr271=	synonymous_variant	7/16	1
CDH3	ENST00000542274.5	c.*551C>A		3_prime_UTR_variant, NMD_transcript_variant	6/15	2
CDH3	ENST00000569036.2	c.*110C>A		3_prime_UTR_variant, NMD_transcript_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95084 AN: 151872 Hom.: 29945 Cov.: 31

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.619

GnomAD3 exomes AF: 0.589 AC: 148079 AN: 251444 Hom.: 44109 AF XY: 0.590 AC XY: 80218 AN XY: 135896

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.579

Gnomad EAS exome AF: 0.608

Gnomad SAS exome AF: 0.542

Gnomad FIN exome AF: 0.603

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.615 AC: 898318 AN: 1461438 Hom.: 277535 Cov.: 49 AF XY: 0.612 AC XY: 445283 AN XY: 727056

Gnomad4 AFR exome AF: 0.669

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.632

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.612

GnomAD4 genome AF: 0.626 AC: 95170 AN: 151990 Hom.: 29975 Cov.: 31 AF XY: 0.621 AC XY: 46129 AN XY: 74294

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.541

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.608

Gnomad4 NFE AF: 0.627

Gnomad4 OTH AF: 0.620

Alfa AF: 0.610 Hom.: 31885

Bravo AF: 0.623

EpiCase AF: 0.621

EpiControl AF: 0.618

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	-0.72
Cadd	Benign	0.44
Dann	Benign	0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs2296408; hg19: chr16-68713823; COSMIC: COSV50554907; COSMIC: COSV50554907;