rs138241615

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004817.4(TJP2):c.185C>T(p.Thr62Met) variant causes a missense change. The variant allele was found at a frequency of 0.00239 in 1,614,136 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 8 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:5O:1

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

TJP2 (HGNC:11828): (tight junction protein 2) This gene encodes a zonula occluden that is a member of the membrane-associated guanylate kinase homolog family. The encoded protein functions as a component of the tight junction barrier in epithelial and endothelial cells and is necessary for proper assembly of tight junctions. Mutations in this gene have been identified in patients with hypercholanemia, and genomic duplication of a 270 kb region including this gene causes autosomal dominant deafness-51. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

TJP2 links:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014933407).

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.185C>T	p.Thr62Met	missense_variant	Exon 3 of 23	ENST00000377245.9	NP_004808.2	Q9UDY2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9 link	c.185C>T	p.Thr62Met	missense_variant	Exon 3 of 23	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 link	c.572C>T	p.Thr191Met	missense_variant	Exon 5 of 25			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

AF:

0.00173

AC:

263

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00273

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00150

AC:

378

AN:

251490

Hom.:

AF XY:

0.00161

AC XY:

219

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00239

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00246

AC:

3592

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1740

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00290

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152268

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00273

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00147

AC:

179

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	TJP2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2025	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	Identified in unrelated patients with intrahepatic cholestasis of pregnancy in published literature (Dixon et al., 2017; Vitale et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33390354, 31450555, 32089630, 29238877, 28924228) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -

Autosomal dominant nonsyndromic hearing loss 51

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

Jun 10, 2024

A very rare variant predicted deleterious by most prediction programs. The type of HL is characteristic for this gene. Classified as likely pathogenic by Deafness Variation Database based on PMID: 29238877 -

Cholestasis, progressive familial intrahepatic, 4;C5542604:Hypercholanemia, familial 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Elsea Laboratory, Baylor College of Medicine

Apr 01, 2020

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 25, 2013

Thr39Met in Exon 4 of TJP2: This variant is not expected to have clinical signi ficance because it has been observed in 0.3% (24/8600) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs138241615). -

TJP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

.;.;T;T;.;.;T;.;T;.;.;.;.;.;.;.;.;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.015

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

.;.;.;.;.;.;L;L;L;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.9

.;D;.;D;.;.;.;D;D;.;.;.;D;.;.;D;.;.

REVEL

Benign

0.15

Sift

Benign

0.063

.;T;.;D;.;.;.;T;D;.;.;.;D;.;.;D;.;.

Sift4G

Uncertain

0.022

.;D;D;D;.;.;.;D;D;.;.;.;D;.;.;D;.;.

Polyphen

0.97, 0.74

.;.;.;.;.;.;D;P;D;.;.;.;.;.;.;.;.;.

Vest4

0.42, 0.42, 0.38, 0.45, 0.39

MVP

0.52

MPC

0.62

ClinPred

0.027

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.53

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over