16-68815659-C-G

Position:

• chr16-68815659-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001317185.2(CDH1):​c.-84C>G variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_001317185.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.320

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09455562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1465C>G	p.Pro489Ala	missense_variant	10/16	ENST00000261769.10	NP_004351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1465C>G	p.Pro489Ala	missense_variant	10/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The p.P489A variant (also known as c.1465C>G), located in coding exon 10 of the CDH1 gene, results from a C to G substitution at nucleotide position 1465. The proline at codon 489 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.69
DEOGEN2	Uncertain	0.77	D;T;T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D;.;.;.;D
REVEL	Benign	0.068
Sift	Benign	0.71	T;.;.;.;T
Sift4G	Benign	0.89	T;T;T;T;T
Polyphen		0.0040	B;.;.;.;.
Vest4		0.26
MutPred		0.39		Loss of catalytic residue at P488 (P = 0.0096);Loss of catalytic residue at P488 (P = 0.0096);.;Loss of catalytic residue at P488 (P = 0.0096);.;
MVP		0.77
MPC		0.25
ClinPred		0.060	T
GERP RS		3.7
Varity_R		0.027
gMVP		0.24

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: chr16-68849562;