dbSNP rs16985493: CDH4:c.170-25056G>A (chr20-61718507-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.170-25056G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 317,434 control chromosomes in the GnomAD database, including 442 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 0.053 ( 256 hom., cov: 34)

Exomes 𝑓: 0.039 ( 186 hom. )

Consequence

CDH4
NM_001794.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.348

Publications

6 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:

ENSG00000179253 (HGNC:58218):

ENSG00000179253 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=-1.03).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH4	NM_001794.5 link	c.170-25056G>A		intron_variant	Intron 2 of 15	ENST00000614565.5	NP_001785.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CDH4	ENST00000614565.5 link	c.170-25056G>A	intron_variant	Intron 2 of 15	1	NM_001794.5	ENSP00000484928.1
ENSG00000179253	ENST00000317652.1 link	n.999C>T	non_coding_transcript_exon_variant	Exon 2 of 2	2
CDH4	ENST00000543233.2 link	c.-53-25056G>A	intron_variant	Intron 1 of 14	2		ENSP00000443301.1
CDH4	ENST00000611855.4 link	c.50-25056G>A	intron_variant	Intron 1 of 14	5		ENSP00000480844.1

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

8069

AN:

152184

Hom.:

254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0753

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0465

Gnomad ASJ

AF:

0.0700

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0530

Gnomad OTH

AF:

0.0593

GnomAD4 exome

AF:

0.0387

AC:

6386

AN:

165132

Hom.:

186

Cov.:

AF XY:

0.0352

AC XY:

3112

AN XY:

88408

show subpopulations

African (AFR)

AF:

0.0818

AC:

405

AN:

4950

American (AMR)

AF:

0.0381

AC:

393

AN:

10320

Ashkenazi Jewish (ASJ)

AF:

0.0687

AC:

261

AN:

3800

East Asian (EAS)

AF:

0.00

AC:

AN:

7962

South Asian (SAS)

AF:

0.00599

AC:

179

AN:

29864

European-Finnish (FIN)

AF:

0.0211

AC:

149

AN:

7076

Middle Eastern (MID)

AF:

0.0842

AC:

AN:

582

European-Non Finnish (NFE)

AF:

0.0494

AC:

4558

AN:

92296

Other (OTH)

AF:

0.0473

AC:

392

AN:

8282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

283

567

850

1134

1417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.0530

AC:

8068

AN:

152302

Hom.:

256

Cov.:

AF XY:

0.0496

AC XY:

3692

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0752

AC:

3124

AN:

41564

American (AMR)

AF:

0.0465

AC:

711

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0700

AC:

243

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00705

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10626

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0529

AC:

3601

AN:

68014

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

399

799

1198

1598

1997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0507

Hom.:

337

Bravo

AF:

0.0558

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.0

(source)

DANN

Benign

0.65

PhyloP100

-0.35

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over