20-61743678-C-G

Variant names:

• chr20-61743678-C-G
• rs767592477
• NM_001794.5:c.285C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001794.5(CDH4):​c.285C>G​(p.Ser95Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S95S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH4 NM_001794.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.71
• Publications: 0 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

CDH4-AS1 (HGNC:40139):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-6.71 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	NM_001794.5	MANE Select	c.285C>G	p.Ser95Ser	synonymous	Exon 3 of 16	NP_001785.2
	CDH4	NM_001252338.2		c.174C>G	p.Ser58Ser	synonymous	Exon 2 of 15	NP_001239267.1
	CDH4	NM_001252339.3		c.63C>G	p.Ser21Ser	synonymous	Exon 2 of 15	NP_001239268.1	P55283-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH4	ENST00000614565.5	TSL:1 MANE Select	c.285C>G	p.Ser95Ser	synonymous	Exon 3 of 16	ENSP00000484928.1	P55283-1
	CDH4	ENST00000543233.2	TSL:2	c.63C>G	p.Ser21Ser	synonymous	Exon 2 of 15	ENSP00000443301.1	P55283-2
	CDH4	ENST00000611855.4	TSL:5	c.114+51C>G		intron	N/A	ENSP00000480844.1	A0A087WX99

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453424 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722018

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 43606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 84418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108308

Other (OTH) AF: 0.00 AC: 0 AN: 60078

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.41
DANN	Benign	0.77
PhyloP100		-6.7

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: rs767592477; hg19: chr20-60318734;