Genetic Variant CDH4:c.169+117051G>A (chr20-61371988-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001794.5(CDH4):c.169+117051G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 152,130 control chromosomes in the GnomAD database, including 41,719 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 41719 hom., cov: 33)

Consequence

CDH4
NM_001794.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.655

Publications

18 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	NM_001794.5	MANE Select	c.169+117051G>A		intron	N/A	NP_001785.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	ENST00000614565.5	TSL:1 MANE Select	c.169+117051G>A		intron	N/A	ENSP00000484928.1	P55283-1

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111605

AN:

152012

Hom.:

41693

Cov.:

show subpopulations

Gnomad AFR

AF:

0.601

Gnomad AMI

AF:

0.713

Gnomad AMR

AF:

0.812

Gnomad ASJ

AF:

0.799

Gnomad EAS

AF:

0.994

Gnomad SAS

AF:

0.889

Gnomad FIN

AF:

0.770

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.753

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.734

AC:

111689

AN:

152130

Hom.:

41719

Cov.:

AF XY:

0.740

AC XY:

55060

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.601

AC:

24934

AN:

41460

American (AMR)

AF:

0.812

AC:

12421

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.799

AC:

2773

AN:

3470

East Asian (EAS)

AF:

0.994

AC:

5145

AN:

5174

South Asian (SAS)

AF:

0.888

AC:

4289

AN:

4832

European-Finnish (FIN)

AF:

0.770

AC:

8149

AN:

10580

Middle Eastern (MID)

AF:

0.796

AC:

234

AN:

294

European-Non Finnish (NFE)

AF:

0.757

AC:

51496

AN:

68000

Other (OTH)

AF:

0.756

AC:

1598

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1474

2947

4421

5894

7368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.758

Hom.:

157993

Bravo

AF:

0.731

Asia WGS

AF:

0.919

AC:

3194

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.5

(source)

DANN

Benign

0.55

PhyloP100

0.66

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over