chr16-66389417-G-C

Position:

chr16-66389417-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001795.5(CDH5):c.676G>C(p.Val226Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,562 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

CDH5
NM_001795.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10410696).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH5	NM_001795.5 linkuse as main transcript	c.676G>C	p.Val226Leu	missense_variant	5/12	ENST00000341529.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH5	ENST00000341529.8 linkuse as main transcript	c.676G>C	p.Val226Leu	missense_variant	5/12	1	NM_001795.5	P1	P33151-1
CDH5	ENST00000649567.1 linkuse as main transcript	c.676G>C	p.Val226Leu	missense_variant	6/13			P1	P33151-1
CDH5	ENST00000563425.2 linkuse as main transcript	c.676G>C	p.Val226Leu	missense_variant	4/6	5
CDH5	ENST00000565334.5 linkuse as main transcript	c.306-1054G>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

250768

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000884

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461274

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

726928

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000766

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000906

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

Jul 30, 2023

The c.676G>C (p.V226L) alteration is located in exon 5 (coding exon 4) of the CDH5 gene. This alteration results from a G to C substitution at nucleotide position 676, causing the valine (V) at amino acid position 226 to be replaced by a leucine (L). 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

0.18

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.47

T;.;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.70

N;N;N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

.;N;.;.

REVEL

Benign

0.22

Sift

Benign

0.083

.;T;.;.

Sift4G

Uncertain

0.012

D;D;.;D

Polyphen

0.99

.;D;D;.

Vest4

0.33

MutPred

0.61

Loss of catalytic residue at V226 (P = 0.0659);Loss of catalytic residue at V226 (P = 0.0659);Loss of catalytic residue at V226 (P = 0.0659);Loss of catalytic residue at V226 (P = 0.0659);

MVP

0.68

MPC

0.62

ClinPred

0.40

GERP RS

4.6

Varity_R

0.20

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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