14-23048351-C-T

Variant names:

• chr14-23048351-C-T
• rs760230215
• NM_144985.4:c.1975G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144985.4(CDH24):​c.1975G>A​(p.Ala659Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH24 NM_144985.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4062607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH24	NM_144985.4	c.1975G>A	p.Ala659Thr	missense_variant	Exon 12 of 13	ENST00000487137.7	NP_659422.2
CDH24	NM_022478.4	c.2089G>A	p.Ala697Thr	missense_variant	Exon 13 of 14		NP_071923.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH24	ENST00000487137.7	c.1975G>A	p.Ala659Thr	missense_variant	Exon 12 of 13	5	NM_144985.4	ENSP00000434821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459772 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726266

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2089G>A (p.A697T) 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 2089, causing the alanine (A) at amino acid position 697 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	0.17
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;T;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;D;.;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	3.2	.;M;.;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;D;.;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.012	D;D;.;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.64
MutPred		0.61		.;Gain of catalytic residue at F698 (P = 0.0038);.;.;Gain of catalytic residue at F698 (P = 0.0038);
MVP		0.89
MPC		1.1
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.30
gMVP		0.70

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

Other links and lift over

dbSNP: rs760230215; hg19: chr14-23517560;