chr14-23048426-C-T

Variant names:

• chr14-23048426-C-T
• rs748984616
• NM_144985.4:c.1900G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144985.4(CDH24):​c.1900G>A​(p.Val634Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CDH24 NM_144985.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.585

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06834608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH24	NM_144985.4	c.1900G>A	p.Val634Ile	missense_variant	Exon 12 of 13	ENST00000487137.7	NP_659422.2
CDH24	NM_022478.4	c.2014G>A	p.Val672Ile	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.1900G>A	p.Val634Ile	missense_variant	Exon 12 of 13	5	NM_144985.4	ENSP00000434821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247788 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134688

Gnomad AFR exome AF: 0.00

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459852 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 726332

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2014G>A (p.V672I) 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 2014, causing the valine (V) at amino acid position 672 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.00084	.;T;.;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.85	T;D;D;.;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.068	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.80	.;N;.;.;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.21	N;N;.;N;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.23	B;P;.;B;P
Vest4		0.26
MutPred		0.46		.;Gain of catalytic residue at L673 (P = 0.0388);.;.;Gain of catalytic residue at L673 (P = 0.0388);
MVP		0.69
MPC		0.56
ClinPred		0.21	T
GERP RS		3.7
Varity_R		0.026
gMVP		0.49

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: rs748984616; hg19: chr14-23517635;