chr20-61773073-C-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001794.5(CDH4):c.467C>G(p.Pro156Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,613,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00035 ( 1 hom. )
Consequence
CDH4
NM_001794.5 missense
NM_001794.5 missense
Scores
16
Clinical Significance
Conservation
PhyloP100: 2.37
Genes affected
CDH4 (HGNC:1763): (cadherin 4) This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Based on studies in chicken and mouse, this cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. Of particular interest are studies showing stable cis-heterodimers of cadherins 2 and 4 in cotransfected cell lines. Previously thought to interact in an exclusively homophilic manner, this is the first evidence of cadherin heterodimerization. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.049159557).
BS2
?
High AC in GnomAd at 26 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH4 | NM_001794.5 | c.467C>G | p.Pro156Arg | missense_variant | 4/16 | ENST00000614565.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH4 | ENST00000614565.5 | c.467C>G | p.Pro156Arg | missense_variant | 4/16 | 1 | NM_001794.5 | P1 | |
CDH4 | ENST00000543233.2 | c.245C>G | p.Pro82Arg | missense_variant | 3/15 | 2 | |||
CDH4 | ENST00000611855.4 | c.185C>G | p.Pro62Arg | missense_variant | 3/15 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152174Hom.: 0 Cov.: 33
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?
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GnomAD3 exomes AF: 0.000236 AC: 59AN: 250100Hom.: 0 AF XY: 0.000244 AC XY: 33AN XY: 135398
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GnomAD4 exome AF: 0.000348 AC: 508AN: 1461440Hom.: 1 Cov.: 31 AF XY: 0.000325 AC XY: 236AN XY: 727018
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GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2021 | The c.467C>G (p.P156R) alteration is located in exon 4 (coding exon 4) of the CDH4 gene. This alteration results from a C to G substitution at nucleotide position 467, causing the proline (P) at amino acid position 156 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
Sift4G
Benign
T;T;T
Polyphen
B;.;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at