Genetic Variant CDH4:p.Glu111Gln (chr20-61743724-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001794.5(CDH4):c.331G>C(p.Glu111Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E111K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CDH4
NM_001794.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0910

Publications

1 publications found

Variant links:

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]

CDH4 Gene-Disease associations (from GenCC):

multiple congenital anomalies/dysmorphic syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CDH4 links:

CDH4-AS1 (HGNC:40139):

CDH4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11435047).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001794.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH4	NM_001794.5	MANE Select	c.331G>C	p.Glu111Gln	missense	Exon 3 of 16	NP_001785.2
CDH4	NM_001252338.2		c.220G>C	p.Glu74Gln	missense	Exon 2 of 15	NP_001239267.1
CDH4	NM_001252339.3		c.109G>C	p.Glu37Gln	missense	Exon 2 of 15	NP_001239268.1	P55283-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH4	ENST00000614565.5	TSL:1 MANE Select	c.331G>C	p.Glu111Gln	missense	Exon 3 of 16	ENSP00000484928.1	P55283-1
CDH4	ENST00000543233.2	TSL:2	c.109G>C	p.Glu37Gln	missense	Exon 2 of 15	ENSP00000443301.1	P55283-2
CDH4	ENST00000611855.4	TSL:5	c.114+97G>C		intron	N/A	ENSP00000480844.1	A0A087WX99

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.77

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.047

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.58

M_CAP

Benign

0.016

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PhyloP100

-0.091

PrimateAI

Benign

0.33

PROVEAN

Benign

0.040

REVEL

Benign

0.048

Sift

Benign

0.23

Sift4G

Benign

0.40

Polyphen

0.074

Vest4

0.093

MutPred

0.58

Gain of MoRF binding (P = 0.0211)

MVP

0.43

ClinPred

0.062

GERP RS

-3.4

Varity_R

0.054

gMVP

0.30

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over