Genetic Variant CDH24:p.Ala603Thr (chr14-23049066-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_144985.4(CDH24):c.1807G>A(p.Ala603Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,612,778 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 4 hom. )

Consequence

CDH24
NM_144985.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

Variant links:

Genes affected

CDH24 (HGNC:14265): (cadherin 24) Enables several functions, including alpha-catenin binding activity; beta-catenin binding activity; and delta-catenin binding activity. Acts upstream of or within cell-cell adhesion. Located in cell-cell junction. [provided by Alliance of Genome Resources, Apr 2022]

CDH24 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=0.2099019).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH24	NM_144985.4 link	c.1807G>A	p.Ala603Thr	missense_variant	Exon 11 of 13	ENST00000487137.7	NP_659422.2	Q86UP0-2
CDH24	NM_022478.4 link	c.1921G>A	p.Ala641Thr	missense_variant	Exon 12 of 14		NP_071923.2	Q86UP0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH24	ENST00000487137.7 link	c.1807G>A	p.Ala603Thr	missense_variant	Exon 11 of 13	5	NM_144985.4	ENSP00000434821.2		Q86UP0-2

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000382

AC:

AN:

246016

Hom.:

AF XY:

0.000410

AC XY:

AN XY:

133986

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.000116

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:

0.000785

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.00111

AC:

1624

AN:

1460402

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

791

AN XY:

726506

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.00139

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000604

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000640

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000363

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1921G>A (p.A641T) alteration is located in exon 12 (coding exon 11) of the CDH24 gene. This alteration results from a G to A substitution at nucleotide position 1921, causing the alanine (A) at amino acid position 641 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

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.098

.;T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;.

M_CAP

Benign

0.033

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.7

.;M;.;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Benign

0.29

Sift

Benign

0.057

T;T;T;T

Sift4G

Benign

0.073

T;T;T;T

Polyphen

0.97

D;D;D;D

Vest4

0.73

MVP

0.83

MPC

1.1

ClinPred

0.24

GERP RS

4.9

Varity_R

0.31

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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