Variant 16-66388411-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_001795.5(CDH5):c.587G>A(p.Gly196Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CDH5
NM_001795.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.27

Variant links:

Genes affected

CDH5 (HGNC:1764): (cadherin 5) This gene encodes a classical cadherin of the cadherin superfamily. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion molecule is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Functioning as a classical cadherin by imparting to cells the ability to adhere in a homophilic manner, this protein plays a role in endothelial adherens junction assembly and maintenance. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. [provided by RefSeq, Nov 2015]

CDH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH5	NM_001795.5 linkuse as main transcript	c.587G>A	p.Gly196Glu	missense_variant	4/12	ENST00000341529.8	NP_001786.2	P33151-1Q59EA3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDH5	ENST00000341529.8 linkuse as main transcript	c.587G>A	p.Gly196Glu	missense_variant	4/12	1	NM_001795.5	ENSP00000344115.3	P33151-1
CDH5	ENST00000649567.1 linkuse as main transcript	c.587G>A	p.Gly196Glu	missense_variant	5/13			ENSP00000497290.1	P33151-1
CDH5	ENST00000563425.2 linkuse as main transcript	c.587G>A	p.Gly196Glu	missense_variant	3/6	5		ENSP00000458878.1	I3L1J2
CDH5	ENST00000565334.5 linkuse as main transcript	n.305+1508G>A		intron_variant		5		ENSP00000456028.1	H3BR11

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460668

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.587G>A (p.G196E) alteration is located in exon 4 (coding exon 3) of the CDH5 gene. This alteration results from a G to A substitution at nucleotide position 587, causing the glycine (G) at amino acid position 196 to be replaced by a glutamic acid (E). 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

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T;T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

T;.;T;T

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Benign

2.0

M;M;M;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.9

.;D;.;.

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Uncertain

0.0070

D;D;.;D

Polyphen

0.99

.;D;D;.

Vest4

0.69

MVP

0.76

MPC

0.79

ClinPred

0.99

GERP RS

5.5

Varity_R

0.85

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over