Genetic Variant CDH4:p.Lys625Met (chr20-61928292-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001794.5(CDH4):c.1874A>T(p.Lys625Met) 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. 15/22 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. K625R) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDH4
NM_001794.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.440

Publications

35 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39095476).

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
CDH4	NM_001794.5	MANE Select	c.1874A>T	p.Lys625Met	missense	Exon 12 of 16	NP_001785.2
CDH4	NM_001252338.2		c.1763A>T	p.Lys588Met	missense	Exon 11 of 15	NP_001239267.1
CDH4	NM_001252339.3		c.1652A>T	p.Lys551Met	missense	Exon 11 of 15	NP_001239268.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH4	ENST00000614565.5	TSL:1 MANE Select	c.1874A>T	p.Lys625Met	missense	Exon 12 of 16	ENSP00000484928.1
CDH4	ENST00000543233.2	TSL:2	c.1652A>T	p.Lys551Met	missense	Exon 11 of 15	ENSP00000443301.1
CDH4	ENST00000611855.4	TSL:5	c.1592A>T	p.Lys531Met	missense	Exon 11 of 15	ENSP00000480844.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1458052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725490

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60374

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.052

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.5

PhyloP100

0.44

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.18

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Polyphen

0.88

Vest4

0.44

MutPred

0.38

Loss of methylation at K625 (P = 0.0191)

MVP

0.60

ClinPred

0.89

GERP RS

-2.0

Varity_R

0.25

gMVP

0.62

Mutation Taster

=87/13

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

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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