chr4-183321999-T-C

Variant names:

• chr4-183321999-T-C
• rs762816911
• NM_001185149.1:c.428A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001185149.1(CLDN24):​c.428A>G​(p.Lys143Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CLDN24 NM_001185149.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.221
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN24	NM_001185149.1	c.428A>G	p.Lys143Arg	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.428A>G	p.Lys143Arg	missense_variant	Exon 1 of 1	6	NM_001185149.1	ENSP00000438400.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 244600 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460822 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 726638

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.000134 AC: 6 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111494

Other (OTH) AF: 0.0000331 AC: 2 AN: 60332

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.000262 AC: 4 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428A>G (p.K143R) alteration is located in exon 1 (coding exon 1) of the CLDN24 gene. This alteration results from a A to G substitution at nucleotide position 428, causing the lysine (K) at amino acid position 143 to be replaced by an arginine (R). 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	0.069
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.0
DANN	Benign	0.74
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.036	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.85	N
PhyloP100		-0.22
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.19
Sift	Benign	0.53	T
Sift4G	Benign	0.52	T
Vest4		0.079
MutPred		0.40		Loss of methylation at K143 (P = 0.0438);
MVP		0.22
MPC		0.52
ClinPred		0.057	T
GERP RS		-9.8
PromoterAI		-0.017	Neutral
Varity_R		0.024
gMVP		0.25
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762816911; hg19: chr4-184243152;