3-138029877-C-T

Variant names:

• chr3-138029877-C-T
• rs1278131062
• NM_016369.4:c.584C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016369.4(CLDN18):​c.584C>T​(p.Ala195Val) 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLDN18 NM_016369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

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]

ACMG classification

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, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN18	NM_016369.4	c.584C>T	p.Ala195Val	missense_variant	Exon 4 of 5	ENST00000183605.10	NP_057453.1
CLDN18	NM_001002026.3	c.584C>T	p.Ala195Val	missense_variant	Exon 4 of 5		NP_001002026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN18	ENST00000183605.10	c.584C>T	p.Ala195Val	missense_variant	Exon 4 of 5	1	NM_016369.4	ENSP00000183605.5
CLDN18	ENST00000343735.8	c.584C>T	p.Ala195Val	missense_variant	Exon 4 of 5	1		ENSP00000340939.4
CLDN18	ENST00000479660.1	n.*25C>T		non_coding_transcript_exon_variant	Exon 3 of 4	2		ENSP00000419732.1
CLDN18	ENST00000479660.1	n.*25C>T		3_prime_UTR_variant	Exon 3 of 4	2		ENSP00000419732.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442882 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.584C>T (p.A195V) alteration is located in exon 4 (coding exon 4) of the CLDN18 gene. This alteration results from a C to T substitution at nucleotide position 584, causing the alanine (A) at amino acid position 195 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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.067	T;D
Polyphen		0.72	P;P
Vest4		0.86
MutPred		0.51		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.97
MPC		0.57
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs1278131062; hg19: chr3-137748719;