16-68813495-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_004360.5(CDH1):c.1320G>T(p.Lys440Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K440E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.51

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_004360.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-68813495-G-T is Pathogenic according to our data. Variant chr16-68813495-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 438812.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-68813495-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1320G>T	p.Lys440Asn	missense_variant, splice_region_variant	9/16	ENST00000261769.10
CDH1	NM_001317185.2	c.-296G>T		5_prime_UTR_variant	9/16
CDH1	NM_001317186.2	c.-500G>T		splice_region_variant, 5_prime_UTR_variant	9/15
CDH1	NM_001317184.2	c.1137+1232G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1320G>T	p.Lys440Asn	missense_variant, splice_region_variant	9/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Blepharocheilodontic syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T;T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;T;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Pathogenic	3.0	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.5	D;.;.;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.72
MutPred		0.77		Loss of ubiquitination at K440 (P = 0.0283);Loss of ubiquitination at K440 (P = 0.0283);Loss of ubiquitination at K440 (P = 0.0283);Loss of ubiquitination at K440 (P = 0.0283);
MVP		0.93
MPC		0.98
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.68		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555515925; hg19: chr16-68847398; COSMIC: COSV55728800; COSMIC: COSV55728800;