20-61718507-G-A

Variant names:

• chr20-61718507-G-A
• rs16985493
• NM_001794.5:c.170-25056G>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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.348
• Publications: 6 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

ENSG00000179253 (HGNC:58218):

ACMG classification

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.

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.170-25056G>A		intron	N/A	NP_001785.2
	CDH4-AS2	NR_147702.1		n.999C>T		non_coding_transcript_exon	Exon 2 of 2
	CDH4	NM_001252338.2		c.59-25056G>A		intron	N/A	NP_001239267.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	ENST00000614565.5	TSL:1 MANE Select	c.170-25056G>A		intron	N/A	ENSP00000484928.1
	ENSG00000179253	ENST00000317652.1	TSL:2	n.999C>T		non_coding_transcript_exon	Exon 2 of 2
	CDH4	ENST00000543233.2	TSL:2	c.-53-25056G>A		intron	N/A	ENSP00000443301.1

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8069 AN: 152184 Hom.: 254 Cov.: 34

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.: 0 AF XY: 0.0352 AC XY: 3112 AN XY: 88408

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: 0 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: 49 AN: 582

European-Non Finnish (NFE) AF: 0.0494 AC: 4558 AN: 92296

Other (OTH) AF: 0.0473 AC: 392 AN: 8282

GnomAD4 genome AF: 0.0530 AC: 8068 AN: 152302 Hom.: 256 Cov.: 34 AF XY: 0.0496 AC XY: 3692 AN XY: 74478

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: 1 AN: 5178

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4826

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10626

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0529 AC: 3601 AN: 68014

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0507 Hom.: 337

Bravo AF: 0.0558

Asia WGS AF: 0.00866 AC: 32 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.65
PhyloP100		-0.35
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: rs16985493; hg19: chr20-60293563;