chr16-83780039-A-G

Position:

chr16-83780039-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001257.5(CDH13):c.1753A>G(p.Ile585Val) variant causes a missense change. The variant allele was found at a frequency of 0.000556 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 1 hom. )

Consequence

CDH13
NM_001257.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29

Variant links:

Genes affected

CDH13 (HGNC:1753): (cadherin 13) This gene encodes a member of the cadherin superfamily. The encoded protein is localized to the surface of the cell membrane and is anchored by a GPI moiety, rather than by a transmembrane domain. The protein lacks the cytoplasmic domain characteristic of other cadherins, and so is not thought to be a cell-cell adhesion glycoprotein. This protein acts as a negative regulator of axon growth during neural differentiation. It also protects vascular endothelial cells from apoptosis due to oxidative stress, and is associated with resistance to atherosclerosis. The gene is hypermethylated in many types of cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2011]

CDH13 links:

HSBP1 (HGNC:5203): (heat shock factor binding protein 1) The heat-shock response is elicited by exposure of cells to thermal and chemical stress and through the activation of HSFs (heat shock factors) results in the elevated expression of heat-shock induced genes. Heat shock factor binding protein 1 (HSBP1), is a 76-amino-acid protein that binds to heat shock factor 1(HSF1), which is a transcription factor involved in the HS response. During HS response, HSF1 undergoes conformational transition from an inert non-DNA-binding monomer to active functional trimers. HSBP1 is nuclear-localized and interacts with the active trimeric state of HSF1 to negatively regulate HSF1 DNA-binding activity. Overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. When overexpressed in C.elegans HSBP1 has severe effects on survival of the animals after thermal and chemical stress consistent with a role of HSBP1 as a negative regulator of heat shock response. [provided by RefSeq, Jul 2008]

HSBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035336703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH13	NM_001257.5 linkuse as main transcript	c.1753A>G	p.Ile585Val	missense_variant	12/14	ENST00000567109.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH13	ENST00000567109.6 linkuse as main transcript	c.1753A>G	p.Ile585Val	missense_variant	12/14	1	NM_001257.5	P1	P55290-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000337

AC:

AN:

249268

Hom.:

AF XY:

0.000362

AC XY:

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.000129

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:

0.000418

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000569

AC:

831

AN:

1461702

Hom.:

Cov.:

AF XY:

0.000562

AC XY:

409

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.000696

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000440

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000589

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.000598

AC:

ExAC

AF:

0.000306

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CDH13-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2022

The CDH13 c.1894A>G variant is predicted to result in the amino acid substitution p.Ile632Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-83813644-A-G), which is likely too common to be consistent with a disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.0086

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.56

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.19

.;N;N

REVEL

Benign

0.056

Sift

Benign

0.86

.;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0030

B;.;.

Vest4

0.17

MVP

0.70

MPC

0.065

ClinPred

0.037

GERP RS

4.4

Varity_R

0.053

gMVP

0.29

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

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