20-61870141-A-G

Variant names:

• chr20-61870141-A-G
• rs2066422
• NM_001794.5:c.878-3587A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001794.5(CDH4):​c.878-3587A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 152,124 control chromosomes in the GnomAD database, including 18,286 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 0.49 (18286 hom., cov: 34)
• Consequence: CDH4 NM_001794.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.94
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.07).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	NM_001794.5	MANE Select	c.878-3587A>G		intron	N/A	NP_001785.2
	CDH4	NM_001252338.2		c.767-3587A>G		intron	N/A	NP_001239267.1
	CDH4	NM_001252339.3		c.656-3587A>G		intron	N/A	NP_001239268.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	ENST00000614565.5	TSL:1 MANE Select	c.878-3587A>G		intron	N/A	ENSP00000484928.1
	CDH4	ENST00000543233.2	TSL:2	c.656-3587A>G		intron	N/A	ENSP00000443301.1
	CDH4	ENST00000611855.4	TSL:5	c.596-3587A>G		intron	N/A	ENSP00000480844.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73936 AN: 152006 Hom.: 18257 Cov.: 34

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.487 AC: 74015 AN: 152124 Hom.: 18286 Cov.: 34 AF XY: 0.483 AC XY: 35947 AN XY: 74370

African (AFR) AF: 0.544 AC: 22600 AN: 41510

American (AMR) AF: 0.491 AC: 7512 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1715 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1589 AN: 5156

South Asian (SAS) AF: 0.457 AC: 2203 AN: 4820

European-Finnish (FIN) AF: 0.403 AC: 4268 AN: 10586

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.480 AC: 32594 AN: 67970

Other (OTH) AF: 0.494 AC: 1044 AN: 2114

Alfa AF: 0.488 Hom.: 58015

Bravo AF: 0.496

Asia WGS AF: 0.387 AC: 1347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.055
DANN	Benign	0.32
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066422; hg19: chr20-60445197;