16-66910341-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004062.4(CDH16):​c.2086G>A​(p.Ala696Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CDH16
NM_004062.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.98
Variant links:
Genes affected
CDH16 (HGNC:1755): (cadherin 16) This gene is a member of the cadherin superfamily, genes encoding calcium-dependent, membrane-associated glycoproteins. Mapped to a previously identified cluster of cadherin genes on chromosome 16q22.1, the gene localizes with superfamily members CDH1, CDH3, CDH5, CDH8 and CDH11. The protein consists of an extracellular domain containing 6 cadherin domains, a transmembrane region and a truncated cytoplasmic domain but lacks the prosequence and tripeptide HAV adhesion recognition sequence typical of most classical cadherins. Expression is exclusively in kidney, where the protein functions as the principal mediator of homotypic cellular recognition, playing a role in the morphogenic direction of tissue development. Alternatively spliced transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH16NM_004062.4 linkc.2086G>A p.Ala696Thr missense_variant Exon 15 of 18 ENST00000299752.9 NP_004053.1 O75309-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH16ENST00000299752.9 linkc.2086G>A p.Ala696Thr missense_variant Exon 15 of 18 1 NM_004062.4 ENSP00000299752.4 O75309-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152192
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250926
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135550
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461518
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000162
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2086G>A (p.A696T) alteration is located in exon 15 (coding exon 14) of the CDH16 gene. This alteration results from a G to A substitution at nucleotide position 2086, causing the alanine (A) at amino acid position 696 to be replaced by a threonine (T). 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
0.076
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
.;T;.;T;.
Eigen
Benign
-0.018
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.23
N
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.16
T;T;T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Uncertain
2.4
.;M;.;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.83
N;N;N;N;N
REVEL
Benign
0.16
Sift
Benign
0.35
T;T;T;T;T
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;D;.;.;.
Vest4
0.22
MutPred
0.32
.;Gain of glycosylation at A696 (P = 0.0085);.;.;.;
MVP
0.79
MPC
0.090
ClinPred
0.54
D
GERP RS
3.9
Varity_R
0.058
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.42
Position offset: -23

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: rs777546645; hg19: chr16-66944244; API