4-183322417-T-G

Variant names:

• chr4-183322417-T-G
• NM_001185149.1:c.10A>C

Variant summary

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

The NM_001185149.1(CLDN24):​c.10A>C​(p.Ile4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CLDN24 NM_001185149.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.358

Genes affected

CLDN24 (HGNC:37200): (claudin 24) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. The protein encoded by this gene is 75% identical to the mouse homolog. This gene is upstream of the CLDN22 gene, which overlaps the WWC2 gene on the opposite strand in the genome.[provided by RefSeq, Aug 2010]

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=0.07404646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN24	NM_001185149.1	c.10A>C	p.Ile4Leu	missense_variant	Exon 1 of 1	ENST00000541814.1	NP_001172078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN24	ENST00000541814.1	c.10A>C	p.Ile4Leu	missense_variant	Exon 1 of 1	6	NM_001185149.1	ENSP00000438400.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450088 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721636

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10A>C (p.I4L) alteration is located in exon 1 (coding exon 1) of the CLDN24 gene. This alteration results from a A to C substitution at nucleotide position 10, causing the isoleucine (I) at amino acid position 4 to be replaced by a leucine (L). 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	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.018
DANN	Benign	0.59
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.27	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.10
Sift	Benign	0.63	T
Sift4G	Benign	0.76	T
Vest4		0.093
MutPred		0.64		Loss of catalytic residue at I4 (P = 0.0291);
MVP		0.26
MPC		0.64
ClinPred		0.13	T
GERP RS		0.90
Varity_R		0.040
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-184243570;