9-69216409-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:6O:1

Conservation

PhyloP100: 4.70

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

cholestasis, progressive familial intrahepatic, 4
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
familial hypercholanemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypercholanemia, familial 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TJP2 links:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 8 AD,Unknown,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

GnomAD2 exomes

AF:

0.00150

AC:

378

AN:

251490

AF XY:

0.00161

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 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

African (AFR)

AF:

0.00111

AC:

AN:

33480

American (AMR)

AF:

0.00112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00290

AC:

3223

AN:

1111988

Other (OTH)

AF:

0.00277

AC:

167

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

187

374

560

747

934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152268

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41552

American (AMR)

AF:

0.00131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00273

AC:

186

AN:

68022

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00224

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:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Feb 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TJP2: BS2 -

Autosomal dominant nonsyndromic hearing loss 51

Pathogenic:1

Jun 10, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 25, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Cholestasis, progressive familial intrahepatic, 4

Benign:1

Dec 22, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

TJP2-related disorder

Benign:1

Feb 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.;.;.;.;.;.;.;.

PhyloP100

4.7

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

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over