4-183321877-T-G

Variant names:

• chr4-183321877-T-G
• rs543472643
• NM_001185149.1:c.550A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001185149.1(CLDN24):​c.550A>C​(p.Asn184His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000808 in 1,571,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: CLDN24 NM_001185149.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0180
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025553942).
• BP6: Variant 4-183321877-T-G is Benign according to our data. Variant chr4-183321877-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3833840.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN24	NM_001185149.1	c.550A>C	p.Asn184His	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.550A>C	p.Asn184His	missense_variant	Exon 1 of 1	6	NM_001185149.1	ENSP00000438400.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 19 AN: 185296 AF XY: 0.0000704

Gnomad AFR exome AF: 0.000681

Gnomad AMR exome AF: 0.0000722

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000773

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000519

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000669 AC: 95 AN: 1419642 Hom.: 0 Cov.: 34 AF XY: 0.0000712 AC XY: 50 AN XY: 702286

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000403 AC: 13 AN: 32282

American (AMR) AF: 0.000105 AC: 4 AN: 38200

Ashkenazi Jewish (ASJ) AF: 0.0000789 AC: 2 AN: 25362

East Asian (EAS) AF: 0.000135 AC: 5 AN: 36902

South Asian (SAS) AF: 0.000160 AC: 13 AN: 81010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.0000495 AC: 54 AN: 1090532

Other (OTH) AF: 0.0000678 AC: 4 AN: 58982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74396

African (AFR) AF: 0.000530 AC: 22 AN: 41520

American (AMR) AF: 0.000393 AC: 6 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

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

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000321

ExAC AF: 0.0000252 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.34
DANN	Benign	0.58
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.097	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.018
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.19
Sift	Benign	0.55	T
Sift4G	Benign	0.54	T
Vest4		0.13
MVP		0.31
MPC		0.67
ClinPred		0.0089	T
GERP RS		-1.3
Varity_R		0.035
gMVP		0.56
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs543472643; hg19: chr4-184243030;