dbSNP rs6061845: CDH4:c.577-20920G>A (chr20-61823748-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.577-20920G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,026 control chromosomes in the GnomAD database, including 30,011 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 0.62 ( 30011 hom., cov: 32)

Consequence

CDH4
NM_001794.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.377

Publications

7 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH4	NM_001794.5 link	c.577-20920G>A		intron_variant	Intron 4 of 15	ENST00000614565.5	NP_001785.2	P55283-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH4	ENST00000614565.5 link	c.577-20920G>A	intron_variant	Intron 4 of 15	1	NM_001794.5	ENSP00000484928.1	P55283-1
CDH4	ENST00000543233.2 link	c.355-20920G>A	intron_variant	Intron 3 of 14	2		ENSP00000443301.1	P55283-2
CDH4	ENST00000611855.4 link	c.295-20920G>A	intron_variant	Intron 3 of 14	5		ENSP00000480844.1	A0A087WX99

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94843

AN:

151908

Hom.:

29975

Cov.:

show subpopulations

Gnomad AFR

AF:

0.637

Gnomad AMI

AF:

0.672

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.738

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.649

Gnomad OTH

AF:

0.620

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

GnomAD4 genome

AF:

0.624

AC:

94929

AN:

152026

Hom.:

30011

Cov.:

AF XY:

0.618

AC XY:

45949

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.638

AC:

26453

AN:

41472

American (AMR)

AF:

0.582

AC:

8894

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.738

AC:

2562

AN:

3472

East Asian (EAS)

AF:

0.367

AC:

1890

AN:

5152

South Asian (SAS)

AF:

0.500

AC:

2410

AN:

4824

European-Finnish (FIN)

AF:

0.614

AC:

6473

AN:

10538

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.649

AC:

44151

AN:

67980

Other (OTH)

AF:

0.614

AC:

1296

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1822

3644

5466

7288

9110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.637

Hom.:

81962

Bravo

AF:

0.621

Asia WGS

AF:

0.452

AC:

1570

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.33

(source)

DANN

Benign

0.77

PhyloP100

-0.38

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over