Genetic Variant CLDN25:p.Ile156Phe (chr11-113780261-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001101389.1(CLDN25):c.466A>T(p.Ile156Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLDN25
NM_001101389.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.76

Variant links:

Genes affected

CLDN25 (HGNC:37218): (claudin 25) 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. [provided by RefSeq, Jun 2010]

CLDN25 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33339584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN25	NM_001101389.1 link	c.466A>T	p.Ile156Phe	missense_variant	Exon 1 of 1	ENST00000453129.3	NP_001094859.1	C9JDP6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN25	ENST00000453129.3 link	c.466A>T	p.Ile156Phe	missense_variant	Exon 1 of 1	6	NM_001101389.1	ENSP00000396304.2		C9JDP6

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249110

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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

AF:

0.00000659

AC:

AN:

151820

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74126

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.69

Eigen

Benign

-0.020

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.18

Sift

Benign

0.094

Sift4G

Uncertain

0.040

Polyphen

0.57

Vest4

0.44

MutPred

0.34

Loss of catalytic residue at P158 (P = 0.0334);

MVP

0.36

MPC

0.034

ClinPred

0.43

GERP RS

3.9

Varity_R

0.20

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over