3-138023679-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016369.4(CLDN18):​c.242C>T​(p.Ala81Val) variant causes a missense change. 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

CLDN18
NM_016369.4 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.94
Variant links:
Genes affected
CLDN18 (HGNC:2039): (claudin 18) 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 upregulated in patients with ulcerative colitis and highly overexpressed in infiltrating ductal adenocarcinomas. PKC/MAPK/AP-1 (protein kinase C/mitogen-activated protein kinase/activator protein-1) dependent pathway regulates the expression of this gene in gastric cells. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jun 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLDN18NM_016369.4 linkc.242C>T p.Ala81Val missense_variant Exon 2 of 5 ENST00000183605.10 NP_057453.1 P56856-1
CLDN18NM_001002026.3 linkc.242C>T p.Ala81Val missense_variant Exon 2 of 5 NP_001002026.1 P56856-2
LOC105374127XR_007096112.1 linkn.-20G>A upstream_gene_variant
LOC105374127XR_924534.3 linkn.-20G>A upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLDN18ENST00000183605.10 linkc.242C>T p.Ala81Val missense_variant Exon 2 of 5 1 NM_016369.4 ENSP00000183605.5 P56856-1
CLDN18ENST00000343735.8 linkc.242C>T p.Ala81Val missense_variant Exon 2 of 5 1 ENSP00000340939.4 P56856-2
CLDN18ENST00000479660.1 linkn.242C>T non_coding_transcript_exon_variant Exon 2 of 4 2 ENSP00000419732.1 F8WEY4

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
Apr 25, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.242C>T (p.A81V) alteration is located in exon 2 (coding exon 2) of the CLDN18 gene. This alteration results from a C to T substitution at nucleotide position 242, causing the alanine (A) at amino acid position 81 to be replaced by a valine (V). 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
0.92
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.64
.;D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.050
T;T
Polyphen
1.0
D;D
Vest4
0.87
MutPred
0.72
Loss of methylation at R80 (P = 0.4432);Loss of methylation at R80 (P = 0.4432);
MVP
0.98
MPC
0.80
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.84
gMVP
0.88

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: chr3-137742521; API