rs1555516534

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000261769.10(CDH1):​c.1588G>C​(p.Ala530Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A530V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

CDH1
ENST00000261769.10 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.1588G>C p.Ala530Pro missense_variant 11/16 ENST00000261769.10 NP_004351.1
CDH1NM_001317184.2 linkuse as main transcriptc.1405G>C p.Ala469Pro missense_variant 10/15 NP_001304113.1
CDH1NM_001317185.2 linkuse as main transcriptc.40G>C p.Ala14Pro missense_variant 11/16 NP_001304114.1
CDH1NM_001317186.2 linkuse as main transcriptc.-254-2699G>C intron_variant NP_001304115.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.1588G>C p.Ala530Pro missense_variant 11/161 NM_004360.5 ENSP00000261769 P1P12830-1
ENST00000563916.1 linkuse as main transcriptn.264-3643C>G intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2017In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CDH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 530 of the CDH1 protein (p.Ala530Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
D;T;T;.;.
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Benign
0.070
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D
MetaSVM
Benign
-0.52
T
MutationAssessor
Benign
1.9
M;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-4.6
D;.;.;.;D
REVEL
Uncertain
0.41
Sift
Uncertain
0.0010
D;.;.;.;D
Sift4G
Uncertain
0.018
D;T;D;T;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.70
MutPred
0.66
Loss of MoRF binding (P = 0.0559);Loss of MoRF binding (P = 0.0559);.;Loss of MoRF binding (P = 0.0559);.;
MVP
0.86
MPC
1.0
ClinPred
0.98
D
GERP RS
5.5
Varity_R
0.83
gMVP
0.68

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555516534; hg19: chr16-68853205; API