NM_004817.4:c.2131T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004817.4(TJP2):c.2131T>C(p.Ser711Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,614,128 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 137 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 112 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.94

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001763612).

BP6

Variant 9-69237088-T-C is Benign according to our data. Variant chr9-69237088-T-C is described in ClinVar as Benign. ClinVar VariationId is 178641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0791 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004817.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TJP2	NM_004817.4	MANE Select	c.2131T>C	p.Ser711Pro	missense	Exon 14 of 23	NP_004808.2
TJP2	NM_001170416.2		c.2224T>C	p.Ser742Pro	missense	Exon 14 of 23	NP_001163887.1
TJP2	NM_001369875.1		c.2143T>C	p.Ser715Pro	missense	Exon 14 of 23	NP_001356804.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TJP2	ENST00000377245.9	TSL:1 MANE Select	c.2131T>C	p.Ser711Pro	missense	Exon 14 of 23	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1		c.2518T>C	p.Ser840Pro	missense	Exon 16 of 25	ENSP00000493780.1
TJP2	ENST00000348208.9	TSL:1	c.2131T>C	p.Ser711Pro	missense	Exon 14 of 21	ENSP00000345893.4

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3543

AN:

152122

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0814

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.00598

AC:

1504

AN:

251490

AF XY:

0.00435

show subpopulations

Gnomad AFR exome

AF:

0.0802

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00235

AC:

3436

AN:

1461888

Hom.:

112

Cov.:

AF XY:

0.00208

AC XY:

1510

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0781

AC:

2616

AN:

33478

American (AMR)

AF:

0.00429

AC:

192

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000233

AC:

259

AN:

1112010

Other (OTH)

AF:

0.00541

AC:

327

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

213

427

640

854

1067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.0233

AC:

3554

AN:

152240

Hom.:

137

Cov.:

AF XY:

0.0224

AC XY:

1670

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0814

AC:

3380

AN:

41532

American (AMR)

AF:

0.00706

AC:

108

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68012

Other (OTH)

AF:

0.0142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

167

334

501

668

835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.00887

Hom.:

100

Bravo

AF:

0.0262

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0853

AC:

376

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00741

AC:

899

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser688Pro in Exon 15 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 8.5% (318/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35797487).

Oct 05, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.12

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-0.63

PhyloP100

2.9

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.7

REVEL

Benign

0.061

Sift

Benign

0.55

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.17

MVP

0.51

MPC

0.25

ClinPred

0.035

GERP RS

4.6

Varity_R

0.057

gMVP

0.47

Mutation Taster

=97/3

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over