chr18-65762981-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004361.5(CDH7):​c.139C>T​(p.Arg47Cys) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CDH7
NM_004361.5 missense

Scores

12
3
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07
Variant links:
Genes affected
CDH7 (HGNC:1766): (cadherin 7) This gene encodes a type II 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 molecule is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Type II (atypical) cadherins are defined based on their lack of a histidine-alanine-valine (HAV) cell adhesion recognition sequence specific to type I cadherins. Cadherins mediate cell-cell binding in a homophilic manner, contributing to the sorting of heterogeneous cell types. Mutations in this gene may be associated with bipolar disease in human patients. This gene is present in a gene cluster on chromosome 18. [provided by RefSeq, May 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH7NM_004361.5 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 12 ENST00000397968.4 NP_004352.2 Q9ULB5
CDH7NM_001362438.2 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 12 NP_001349367.1
CDH7NM_033646.4 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 12 NP_387450.1 Q9ULB5
CDH7NM_001317214.3 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 11 NP_001304143.1 Q9ULB5F5H5X9Q8IY78

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH7ENST00000397968.4 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 12 1 NM_004361.5 ENSP00000381058.2 Q9ULB5
CDH7ENST00000323011.7 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 12 1 ENSP00000319166.3 Q9ULB5
CDH7ENST00000536984.6 linkc.139C>T p.Arg47Cys missense_variant Exon 2 of 11 1 ENSP00000443030.2 F5H5X9
CDH7ENST00000581601.1 linkn.-27C>T upstream_gene_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.139C>T (p.R47C) alteration is located in exon 2 (coding exon 1) of the CDH7 gene. This alteration results from a C to T substitution at nucleotide position 139, causing the arginine (R) at amino acid position 47 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.51
D;T;D
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Benign
0.035
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.81
L;.;L
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-6.9
D;D;D
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.80
MutPred
0.86
Loss of disorder (P = 0.0108);Loss of disorder (P = 0.0108);Loss of disorder (P = 0.0108);
MVP
0.71
MPC
1.3
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.68
gMVP
0.95

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: rs1916243226; hg19: chr18-63430217; COSMIC: COSV59881758; COSMIC: COSV59881758; API