NM_001793.6:c.1689G>C

Variant names:

• chr16-68687630-G-C
• rs1126933
• NM_001793.6:c.1689G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001793.6(CDH3):​c.1689G>C​(p.Gln563His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,374 control chromosomes in the GnomAD database, including 131,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q563Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (9276 hom., cov: 30)
  • Exomes 𝑓: 0.40 (122580 hom.)
• Consequence: CDH3 NM_001793.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.134
• Publications: 40 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen
• congenital hypotrichosis with juvenile macular dystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6865134E-4).
• BP6: Variant 16-68687630-G-C is Benign according to our data. Variant chr16-68687630-G-C is described in ClinVar as Benign. ClinVar VariationId is 320245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001793.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH3	NM_001793.6	MANE Select	c.1689G>C	p.Gln563His	missense	Exon 12 of 16	NP_001784.2
	CDH3	NM_001317195.3		c.1689G>C	p.Gln563His	missense	Exon 12 of 16	NP_001304124.1	P22223-2
	CDH3	NM_001317196.2		c.1524G>C	p.Gln508His	missense	Exon 11 of 15	NP_001304125.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH3	ENST00000264012.9	TSL:1 MANE Select	c.1689G>C	p.Gln563His	missense	Exon 12 of 16	ENSP00000264012.4	P22223-1
	CDH3	ENST00000429102.6	TSL:1	c.1689G>C	p.Gln563His	missense	Exon 12 of 16	ENSP00000398485.2	P22223-2
	CDH3	ENST00000914963.1		c.1719G>C	p.Gln573His	missense	Exon 12 of 16	ENSP00000585022.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48025 AN: 151882 Hom.: 9275 Cov.: 30

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.373 AC: 93768 AN: 251448 AF XY: 0.378

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.370

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.404 AC: 590537 AN: 1461374 Hom.: 122580 Cov.: 43 AF XY: 0.403 AC XY: 292789 AN XY: 727034

African (AFR) AF: 0.0691 AC: 2312 AN: 33476

American (AMR) AF: 0.350 AC: 15634 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 9665 AN: 26134

East Asian (EAS) AF: 0.543 AC: 21530 AN: 39678

South Asian (SAS) AF: 0.344 AC: 29713 AN: 86254

European-Finnish (FIN) AF: 0.407 AC: 21726 AN: 53404

Middle Eastern (MID) AF: 0.279 AC: 1607 AN: 5768

European-Non Finnish (NFE) AF: 0.418 AC: 465180 AN: 1111552

Other (OTH) AF: 0.384 AC: 23170 AN: 60388

GnomAD4 genome AF: 0.316 AC: 48030 AN: 152000 Hom.: 9276 Cov.: 30 AF XY: 0.317 AC XY: 23562 AN XY: 74262

African (AFR) AF: 0.0841 AC: 3489 AN: 41502

American (AMR) AF: 0.350 AC: 5354 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3472

East Asian (EAS) AF: 0.510 AC: 2613 AN: 5122

South Asian (SAS) AF: 0.338 AC: 1625 AN: 4804

European-Finnish (FIN) AF: 0.413 AC: 4368 AN: 10566

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28206 AN: 67942

Other (OTH) AF: 0.317 AC: 667 AN: 2104

Alfa AF: 0.387 Hom.: 8835

Bravo AF: 0.303

TwinsUK AF: 0.411 AC: 1523

ALSPAC AF: 0.429 AC: 1654

ESP6500AA AF: 0.0901 AC: 396

ESP6500EA AF: 0.417 AC: 3590

ExAC AF: 0.366 AC: 44402

Asia WGS AF: 0.350 AC: 1218 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.398

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	EEM syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.5
DANN	Benign	0.68
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.00017	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.13
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.062
Sift	Benign	0.33	T
Sift4G	Benign	0.44	T
Polyphen		0.029	B
Vest4		0.30
MutPred		0.24		Gain of catalytic residue at L565 (P = 0.0792)
MPC		0.76
ClinPred		0.0029	T
GERP RS		-3.3
Varity_R		0.064
gMVP		0.75
Mutation Taster		=98/2	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: rs1126933; hg19: chr16-68721533; COSMIC: COSV50554947; COSMIC: COSV50554947;