chr16-68813339-G-T

Position:

• chr16-68813339-G-T

Variant summary

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

The NM_004360.5(CDH1):​c.1164G>T​(p.Glu388Asp) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.582

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]

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=0.20834824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1164G>T	p.Glu388Asp	missense_variant	9/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2	c.-452G>T		5_prime_UTR_variant	9/16		NP_001304114.1
CDH1	NM_001317186.2	c.-656G>T		5_prime_UTR_variant	9/15		NP_001304115.1
CDH1	NM_001317184.2	c.1137+1076G>T		intron_variant			NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1164G>T	p.Glu388Asp	missense_variant	9/16	1	NM_004360.5	ENSP00000261769	P1

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

Oct 15, 2019

The p.E388D variant (also known as c.1164G>T), located in coding exon 9 of the CDH1 gene, results from a G to T substitution at nucleotide position 1164. The glutamic acid at codon 388 is replaced by aspartic acid, 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	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;.;.;.
REVEL	Benign	0.092
Sift	Benign	0.039	D;.;.;.
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.028	B;.;.;.
Vest4		0.32
MutPred		0.39		Loss of catalytic residue at E388 (P = 0.0769);Loss of catalytic residue at E388 (P = 0.0769);Loss of catalytic residue at E388 (P = 0.0769);Loss of catalytic residue at E388 (P = 0.0769);
MVP		0.73
MPC		0.27
ClinPred		0.16	T
GERP RS		-1.1
Varity_R		0.19
gMVP		0.53

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: rs774875972; hg19: chr16-68847242;