NM_004360.5:c.2028C>G

Variant names:

• chr16-68823490-C-G
• NM_004360.5:c.2028C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PS1 PM2 BP4_Moderate

The NM_004360.5(CDH1):​c.2028C>G​(p.Asp676Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.521

Genes affected

CDH1 (HGNC:1748): (cadherin 1) 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. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

ENSG00000260798 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS1: Transcript NM_004360.5 (CDH1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1268506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2028C>G	p.Asp676Glu	missense_variant	Exon 13 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1845C>G	p.Asp615Glu	missense_variant	Exon 12 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.480C>G	p.Asp160Glu	missense_variant	Exon 13 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.63C>G	p.Asp21Glu	missense_variant	Exon 12 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2028C>G	p.Asp676Glu	missense_variant	Exon 13 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Jan 09, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T;T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.26	T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.99	N;.;N
REVEL	Benign	0.098
Sift	Benign	0.57	T;.;T
Sift4G	Benign	0.99	T;T;T
Polyphen		0.010	B;.;.
Vest4		0.064
MutPred		0.42		Gain of methylation at K675 (P = 0.0946);.;.;
MVP		0.76
MPC		0.25
ClinPred		0.20	T
GERP RS		6.0
Varity_R		0.27
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68857393;