4-183319967-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001111319.3(CLDN22):​c.252G>A​(p.Met84Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CLDN22
NM_001111319.3 missense

Scores

5
12
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01
Variant links:
Genes affected
CLDN22 (HGNC:2044): (claudin 22) 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. This gene is intronless and overlaps the 3' UTR of the WWC2 gene (GeneID: 80014) on the opposite strand. [provided by RefSeq, Aug 2010]
WWC2 (HGNC:24148): (WW and C2 domain containing 2) This gene encodes a member of the WW-and-C2-domain-containing family of proteins. Members of this family have two N-terminal WW domains that mediate binding to target proteins harboring L/PPxY motifs, an internal C2 domain for membrane association, and C-terminal alpha protein kinase C binding sites and class III PDZ domain-interaction motifs. Proteins of this family are able to form homo- and heterodimers and to modulate hippo pathway signaling. [provided by RefSeq, Sep 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN22NM_001111319.3 linkc.252G>A p.Met84Ile missense_variant Exon 1 of 1 ENST00000323319.7 NP_001104789.1 Q8N7P3
WWC2NM_024949.6 linkc.*4238C>T 3_prime_UTR_variant Exon 23 of 23 ENST00000403733.8 NP_079225.5 Q6AWC2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN22ENST00000323319.7 linkc.252G>A p.Met84Ile missense_variant Exon 1 of 1 6 NM_001111319.3 ENSP00000318113.5 Q8N7P3
WWC2ENST00000403733.8 linkc.*4238C>T 3_prime_UTR_variant Exon 23 of 23 5 NM_024949.6 ENSP00000384222.3 Q6AWC2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 29, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.252G>A (p.M84I) alteration is located in exon 1 (coding exon 1) of the CLDN22 gene. This alteration results from a G to A substitution at nucleotide position 252, causing the methionine (M) at amino acid position 84 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
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.049
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.4
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.038
D
Polyphen
0.97
D
Vest4
0.38
MutPred
0.79
Loss of phosphorylation at S80 (P = 0.2334);
MVP
0.93
MPC
0.82
ClinPred
0.96
D
GERP RS
6.1
Varity_R
0.74
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-184241120; API