Genetic Variant CDH24:p.Ala700Thr (chr14-23048228-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144985.4(CDH24):c.2098G>A(p.Ala700Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,302,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CDH24
NM_144985.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.581

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07169908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH24	NM_144985.4 link	c.2098G>A	p.Ala700Thr	missense_variant	Exon 12 of 13	ENST00000487137.7	NP_659422.2	Q86UP0-2
CDH24	NM_022478.4 link	c.2212G>A	p.Ala738Thr	missense_variant	Exon 13 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.2098G>A	p.Ala700Thr	missense_variant	Exon 12 of 13	5	NM_144985.4	ENSP00000434821.2		Q86UP0-2

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

150468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000535

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000113

AC:

AN:

1151632

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

558478

show subpopulations

Gnomad4 AFR exome

AF:

0.000404

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000320

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000153

AC:

AN:

150576

Hom.:

Cov.:

AF XY:

0.0000816

AC XY:

AN XY:

73572

show subpopulations

Gnomad4 AFR

AF:

0.000557

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2212G>A (p.A738T) alteration is located in exon 13 (coding exon 12) of the CDH24 gene. This alteration results from a G to A substitution at nucleotide position 2212, causing the alanine (A) at amino acid position 738 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

0.093

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0010

.;T;.;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.32

T;T;T;.;.

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.072

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.71

.;N;.;.;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.59

N;N;.;N;N

REVEL

Benign

0.056

Sift

Benign

0.50

T;T;.;T;T

Sift4G

Benign

0.58

T;T;T;T;T

Polyphen

0.0

B;B;.;B;B

Vest4

0.19

MutPred

0.35

.;Gain of catalytic residue at P734 (P = 5e-04);.;.;Gain of catalytic residue at P734 (P = 5e-04);

MVP

0.66

MPC

1.5

ClinPred

0.043

GERP RS

3.0

Varity_R

0.064

gMVP

0.21

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