3-138023679-C-T

Variant names:

• chr3-138023679-C-T
• NM_016369.4:c.242C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94

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]

LOC105374127 (HGNC:):

ACMG classification

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
CLDN18	NM_016369.4	c.242C>T	p.Ala81Val	missense_variant	Exon 2 of 5	ENST00000183605.10	NP_057453.1
CLDN18	NM_001002026.3	c.242C>T	p.Ala81Val	missense_variant	Exon 2 of 5		NP_001002026.1
LOC105374127	XR_007096112.1	n.-20G>A		upstream_gene_variant
LOC105374127	XR_924534.3	n.-20G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN18	ENST00000183605.10	c.242C>T	p.Ala81Val	missense_variant	Exon 2 of 5	1	NM_016369.4	ENSP00000183605.5
CLDN18	ENST00000343735.8	c.242C>T	p.Ala81Val	missense_variant	Exon 2 of 5	1		ENSP00000340939.4
CLDN18	ENST00000479660.1	n.242C>T		non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000419732.1

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

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;