chr7-90412794-A-C

Variant names:

• chr7-90412794-A-C
• NM_001185072.3:c.118A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001185072.3(CLDN12):​c.118A>C​(p.Thr40Pro) variant causes a missense change involving the alteration of a 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: CLDN12 NM_001185072.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.50
• Publications: 0 publications found

Genes affected

CLDN12 (HGNC:2034): (claudin 12) 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 expressed in the inner ear and bladder epithelium, and it is over-expressed in colorectal carcinomas. This protein and claudin 2 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Multiple alternatively spliced transcript variants encoding the same protein have been found.[provided by RefSeq, Sep 2011]

ENSG00000273299 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN12	NM_001185072.3	c.118A>C	p.Thr40Pro	missense_variant	Exon 4 of 4	ENST00000496677.6	NP_001172001.1
CLDN12	NM_001185073.3	c.118A>C	p.Thr40Pro	missense_variant	Exon 3 of 3		NP_001172002.1
CLDN12	NM_012129.5	c.118A>C	p.Thr40Pro	missense_variant	Exon 3 of 3		NP_036261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN12	ENST00000496677.6	c.118A>C	p.Thr40Pro	missense_variant	Exon 4 of 4	1	NM_001185072.3	ENSP00000419053.1

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 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.118A>C (p.T40P) alteration is located in exon 4 (coding exon 1) of the CLDN12 gene. This alteration results from a A to C substitution at nucleotide position 118, causing the threonine (T) at amino acid position 40 to be replaced by a proline (P). 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	0.81
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;.;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T;.;T;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.2	.;M;.;M;.
PhyloP100		8.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.5	N;N;N;N;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;D;.
Vest4		0.63
MutPred		0.70		Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);
MVP		0.95
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.95
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

hg19: chr7-90042108;