20-61773073-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001794.5(CDH4):c.467C>G(p.Pro156Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,613,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049159557).
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH4	NM_001794.5	c.467C>G	p.Pro156Arg	missense_variant	4/16	ENST00000614565.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH4	ENST00000614565.5	c.467C>G	p.Pro156Arg	missense_variant	4/16	1	NM_001794.5	P1
CDH4	ENST00000543233.2	c.245C>G	p.Pro82Arg	missense_variant	3/15	2
CDH4	ENST00000611855.4	c.185C>G	p.Pro62Arg	missense_variant	3/15	5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000236 AC: 59 AN: 250100 Hom.: 0 AF XY: 0.000244 AC XY: 33 AN XY: 135398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461440 Hom.: 1 Cov.: 31 AF XY: 0.000325 AC XY: 236 AN XY: 727018

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.000282

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.467C>G (p.P156R) alteration is located in exon 4 (coding exon 4) of the CDH4 gene. This alteration results from a C to G substitution at nucleotide position 467, causing the proline (P) at amino acid position 156 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Benign	0.42
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.;.
MutationTaster	Benign	0.78	D;D
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.59	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.12
MVP		0.31
ClinPred		0.020	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs767954523; hg19: chr20-60348129;