rs752349229

Variant summary

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

The NM_004360.5(CDH1):​c.2375T>A​(p.Met792Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

CDH1
NM_004360.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12
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, 0.784

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.2375T>A p.Met792Lys missense_variant 15/16 ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61
CDH1NM_001317184.2 linkuse as main transcriptc.2192T>A p.Met731Lys missense_variant 14/15 NP_001304113.1 P12830-2B3GN61
CDH1NM_001317185.2 linkuse as main transcriptc.827T>A p.Met276Lys missense_variant 15/16 NP_001304114.1 P12830B3GN61Q9UII7
CDH1NM_001317186.2 linkuse as main transcriptc.410T>A p.Met137Lys missense_variant 14/15 NP_001304115.1 P12830B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.2375T>A p.Met792Lys missense_variant 15/161 NM_004360.5 ENSP00000261769.4 P12830-1

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
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 11, 2024The p.M792K variant (also known as c.2375T>A), located in coding exon 15 of the CDH1 gene, results from a T to A substitution at nucleotide position 2375. The methionine at codon 792 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.027
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Uncertain
0.44
T;T;.
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.56
T;T;T
M_CAP
Uncertain
0.086
D
MetaRNN
Pathogenic
0.78
D;D;D
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
1.9
L;.;.
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-3.1
D;.;D
REVEL
Uncertain
0.45
Sift
Benign
0.28
T;.;T
Sift4G
Benign
0.31
T;T;T
Polyphen
0.80
P;.;.
Vest4
0.62
MutPred
0.64
Gain of methylation at M792 (P = 0.0222);.;.;
MVP
0.90
MPC
0.92
ClinPred
0.80
D
GERP RS
4.9
Varity_R
0.60
gMVP
0.60

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: chr16-68863636; API