3-138029810-G-T

Variant names:

• chr3-138029810-G-T
• rs1378543153
• NM_016369.4:c.517G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_016369.4(CLDN18):​c.517G>T​(p.Ala173Ser) 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 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A173T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLDN18 NM_016369.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.531
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.188335).
• BP6: Variant 3-138029810-G-T is Benign according to our data. Variant chr3-138029810-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3145482.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN18	NM_016369.4	MANE Select	c.517G>T	p.Ala173Ser	missense	Exon 4 of 5	NP_057453.1	P56856-1
	CLDN18	NM_001002026.3		c.517G>T	p.Ala173Ser	missense	Exon 4 of 5	NP_001002026.1	P56856-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLDN18	ENST00000183605.10	TSL:1 MANE Select	c.517G>T	p.Ala173Ser	missense	Exon 4 of 5	ENSP00000183605.5	P56856-1
	CLDN18	ENST00000343735.8	TSL:1	c.517G>T	p.Ala173Ser	missense	Exon 4 of 5	ENSP00000340939.4	P56856-2
	CLDN18	ENST00000862384.1		c.352G>T	p.Ala118Ser	missense	Exon 3 of 4	ENSP00000532443.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.8
DANN	Benign	0.51
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.53
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.62		Gain of glycosylation at A173 (P = 0.0692)
MVP		0.83
MPC		0.19
ClinPred		0.047	T
GERP RS		0.54
Varity_R		0.071
gMVP		0.41
Mutation Taster		=93/7	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: rs1378543153; hg19: chr3-137748652;