rs6142884

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001794.5(CDH4):c.1874A>G(p.Lys625Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,610,020 control chromosomes in the GnomAD database, including 234,382 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 Benign (no stars).

Frequency

Genomes: 𝑓 0.49 ( 19615 hom., cov: 34)

Exomes 𝑓: 0.54 ( 214767 hom. )

Consequence

CDH4
NM_001794.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.599209E-7).

BP6

Variant 20-61928292-A-G is Benign according to our data. Variant chr20-61928292-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060356.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

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>G	p.Lys625Arg	missense	Exon 12 of 16	NP_001785.2
CDH4	NM_001252338.2		c.1763A>G	p.Lys588Arg	missense	Exon 11 of 15	NP_001239267.1
CDH4	NM_001252339.3		c.1652A>G	p.Lys551Arg	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>G	p.Lys625Arg	missense	Exon 12 of 16	ENSP00000484928.1
CDH4	ENST00000543233.2	TSL:2	c.1652A>G	p.Lys551Arg	missense	Exon 11 of 15	ENSP00000443301.1
CDH4	ENST00000611855.4	TSL:5	c.1592A>G	p.Lys531Arg	missense	Exon 11 of 15	ENSP00000480844.1

Frequencies

GnomAD3 genomes

AF:

0.491

AC:

74575

AN:

152030

Hom.:

19594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.466

Gnomad AMR

AF:

0.585

Gnomad ASJ

AF:

0.492

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.703

Gnomad FIN

AF:

0.575

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.517

Gnomad OTH

AF:

0.482

GnomAD2 exomes

AF:

0.576

AC:

142748

AN:

247634

AF XY:

0.577

show subpopulations

Gnomad AFR exome

AF:

0.312

Gnomad AMR exome

AF:

0.669

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.849

Gnomad FIN exome

AF:

0.586

Gnomad NFE exome

AF:

0.518

Gnomad OTH exome

AF:

0.548

GnomAD4 exome

AF:

0.536

AC:

781247

AN:

1457872

Hom.:

214767

Cov.:

AF XY:

0.540

AC XY:

391855

AN XY:

725414

show subpopulations

African (AFR)

AF:

0.308

AC:

10314

AN:

33474

American (AMR)

AF:

0.657

AC:

29370

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12815

AN:

26132

East Asian (EAS)

AF:

0.859

AC:

34092

AN:

39700

South Asian (SAS)

AF:

0.686

AC:

59169

AN:

86258

European-Finnish (FIN)

AF:

0.588

AC:

29159

AN:

49592

Middle Eastern (MID)

AF:

0.508

AC:

2932

AN:

5768

European-Non Finnish (NFE)

AF:

0.514

AC:

571110

AN:

1111860

Other (OTH)

AF:

0.535

AC:

32286

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

23265

46531

69796

93062

116327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16574

33148

49722

66296

82870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.490

AC:

74618

AN:

152148

Hom.:

19615

Cov.:

AF XY:

0.500

AC XY:

37182

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.321

AC:

13331

AN:

41512

American (AMR)

AF:

0.586

AC:

8962

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.492

AC:

1707

AN:

3470

East Asian (EAS)

AF:

0.847

AC:

4388

AN:

5178

South Asian (SAS)

AF:

0.703

AC:

3395

AN:

4826

European-Finnish (FIN)

AF:

0.575

AC:

6096

AN:

10594

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.517

AC:

35162

AN:

67968

Other (OTH)

AF:

0.487

AC:

1024

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1880

3760

5639

7519

9399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.512

Hom.:

100289

Bravo

AF:

0.479

TwinsUK

AF:

0.513

AC:

1901

ALSPAC

AF:

0.518

AC:

1998

ESP6500AA

AF:

0.316

AC:

1393

ESP6500EA

AF:

0.516

AC:

4434

ExAC

AF:

0.571

AC:

69270

Asia WGS

AF:

0.757

AC:

2633

AN:

3478

EpiCase

AF:

0.502

EpiControl

AF:

0.497

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CDH4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.9

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.052

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.63

MetaRNN

Benign

6.6e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.85

PhyloP100

0.44

PrimateAI

Benign

0.38

PROVEAN

Benign

0.30

REVEL

Benign

0.052

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.050

ClinPred

0.0025

GERP RS

-2.0

Varity_R

0.050

gMVP

0.33

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over