20-61823748-G-A

Variant names:

• chr20-61823748-G-A
• rs6061845
• NM_001794.5:c.577-20920G>A

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.377
• Publications: 7 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 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.577-20920G>A		intron	N/A	NP_001785.2
	CDH4	NM_001252338.2		c.466-20920G>A		intron	N/A	NP_001239267.1
	CDH4	NM_001252339.3		c.355-20920G>A		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.577-20920G>A		intron	N/A	ENSP00000484928.1
	CDH4	ENST00000543233.2	TSL:2	c.355-20920G>A		intron	N/A	ENSP00000443301.1
	CDH4	ENST00000611855.4	TSL:5	c.295-20920G>A		intron	N/A	ENSP00000480844.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94843 AN: 151908 Hom.: 29975 Cov.: 32

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.: 32 AF XY: 0.618 AC XY: 45949 AN XY: 74302

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.33
DANN	Benign	0.77
PhyloP100		-0.38
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: rs6061845; hg19: chr20-60398804;