16-66389417-G-C

Variant summary

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

The NM_001795.5(CDH5):ā€‹c.676G>Cā€‹(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 (ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 33)
Exomes š‘“: 0.000051 ( 1 hom. )

Consequence

CDH5
NM_001795.5 missense

Scores

7
12

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]

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
CDH5NM_001795.5 linkuse as main transcriptc.676G>C p.Val226Leu missense_variant 5/12 ENST00000341529.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH5ENST00000341529.8 linkuse as main transcriptc.676G>C p.Val226Leu missense_variant 5/121 NM_001795.5 P1P33151-1
CDH5ENST00000649567.1 linkuse as main transcriptc.676G>C p.Val226Leu missense_variant 6/13 P1P33151-1
CDH5ENST00000563425.2 linkuse as main transcriptc.676G>C p.Val226Leu missense_variant 4/65
CDH5ENST00000565334.5 linkuse as main transcriptc.306-1054G>C intron_variant, NMD_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152170
Hom.:
0
Cov.:
33
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:
28
AN:
250768
Hom.:
0
AF XY:
0.000170
AC XY:
23
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:
74
AN:
1461274
Hom.:
1
Cov.:
31
AF XY:
0.0000798
AC XY:
58
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:
6
AN:
152288
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
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:
11

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 submitterclinical testingAmbry GeneticsJul 30, 2023The 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
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
23
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
D
LIST_S2
Benign
0.47
T;.;T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.10
T;T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
0.70
N;N;N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
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
T
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.

Other links and lift over

dbSNP: rs140053187; hg19: chr16-66423320; API