rs371601956

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_004360.5(CDH1):ā€‹c.627A>Cā€‹(p.Arg209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.410
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a domain Cadherin 1 (size 107) in uniprot entity CADH1_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_004360.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33259994).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.627A>C p.Arg209Ser missense_variant 5/16 ENST00000261769.10 NP_004351.1
CDH1NM_001317184.2 linkuse as main transcriptc.627A>C p.Arg209Ser missense_variant 5/15 NP_001304113.1
CDH1NM_001317185.2 linkuse as main transcriptc.-989A>C 5_prime_UTR_variant 5/16 NP_001304114.1
CDH1NM_001317186.2 linkuse as main transcriptc.-1193A>C 5_prime_UTR_variant 5/15 NP_001304115.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.627A>C p.Arg209Ser missense_variant 5/161 NM_004360.5 ENSP00000261769 P1P12830-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461868
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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), LabcorpNov 07, 2021In 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 567386). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 209 of the CDH1 protein (p.Arg209Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Uncertain
0.047
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
23
DANN
Benign
0.85
DEOGEN2
Benign
0.29
T;T;T;.;.
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.5
L;.;.;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-2.4
N;.;.;.;N
REVEL
Benign
0.26
Sift
Benign
0.37
T;.;.;.;T
Sift4G
Benign
0.23
T;T;T;T;T
Polyphen
0.99
D;.;.;.;.
Vest4
0.64
MutPred
0.55
Gain of glycosylation at R209 (P = 0.1126);Gain of glycosylation at R209 (P = 0.1126);Gain of glycosylation at R209 (P = 0.1126);Gain of glycosylation at R209 (P = 0.1126);Gain of glycosylation at R209 (P = 0.1126);
MVP
0.81
MPC
0.72
ClinPred
0.81
D
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.59
gMVP
0.50

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: rs371601956; hg19: chr16-68842691; API