20-61928292-A-G

Position:

• chr20-61928292-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001794.5(CDH4):​c.1874A>G​(p.Lys625Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,610,020 control chromosomes in the GnomAD database, including 234,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.49 (19615 hom., cov: 34)
  • Exomes 𝑓: 0.54 (214767 hom.)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.440

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.599209E-7).
• BP6: Variant 20-61928292-A-G is Benign according to our data. Variant chr20-61928292-A-G is described in ClinVar as [Benign]. Clinvar id is 3060356.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH4	NM_001794.5	c.1874A>G	p.Lys625Arg	missense_variant	12/16	ENST00000614565.5	NP_001785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH4	ENST00000614565.5	c.1874A>G	p.Lys625Arg	missense_variant	12/16	1	NM_001794.5	ENSP00000484928	P1
CDH4	ENST00000543233.2	c.1652A>G	p.Lys551Arg	missense_variant	11/15	2		ENSP00000443301
CDH4	ENST00000611855.4	c.1592A>G	p.Lys531Arg	missense_variant	11/15	5		ENSP00000480844

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74575 AN: 152030 Hom.: 19594 Cov.: 34

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.482

GnomAD3 exomes AF: 0.576 AC: 142748 AN: 247634 Hom.: 43408 AF XY: 0.577 AC XY: 77482 AN XY: 134276

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.849

Gnomad SAS exome AF: 0.690

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.548

GnomAD4 exome AF: 0.536 AC: 781247 AN: 1457872 Hom.: 214767 Cov.: 56 AF XY: 0.540 AC XY: 391855 AN XY: 725414

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.657

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.859

Gnomad4 SAS exome AF: 0.686

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.535

GnomAD4 genome AF: 0.490 AC: 74618 AN: 152148 Hom.: 19615 Cov.: 34 AF XY: 0.500 AC XY: 37182 AN XY: 74396

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.847

Gnomad4 SAS AF: 0.703

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.487

Alfa AF: 0.518 Hom.: 51413

Bravo AF: 0.479

TwinsUK AF: 0.513 AC: 1901

ALSPAC AF: 0.518 AC: 1998

ESP6500AA AF: 0.316 AC: 1393

ESP6500EA AF: 0.516 AC: 4434

ExAC AF: 0.571 AC: 69270

Asia WGS AF: 0.757 AC: 2633 AN: 3478

EpiCase AF: 0.502

EpiControl AF: 0.497

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CDH4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.9
DANN	Benign	0.22
DEOGEN2	Benign	0.052	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	6.6e-7	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.85	N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.30	.;.;N
REVEL	Benign	0.052
Sift	Benign	1.0	.;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.050
ClinPred		0.0025	T
GERP RS		-2.0
Varity_R		0.050
gMVP		0.33

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: rs6142884; hg19: chr20-60503350; COSMIC: COSV64641244;