NM_004817.4:c.1091C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_004817.4(TJP2):c.1091C>T(p.Thr364Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,060 control chromosomes in the GnomAD database, including 9 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T364A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 7 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.75

Publications

3 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007243693).

BP6

Variant 9-69226056-C-T is Benign according to our data. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69226056-C-T is described in CliVar as Benign. Clinvar id is 178639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00581 (885/152224) while in subpopulation AFR AF = 0.0194 (806/41514). AF 95% confidence interval is 0.0183. There are 2 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,Unknown,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.1091C>T	p.Thr364Met	missense_variant	Exon 7 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.1091C>T	p.Thr364Met	missense_variant	Exon 7 of 23	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 link	c.1478C>T	p.Thr493Met	missense_variant	Exon 9 of 25			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

AF:

0.00583

AC:

887

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00171

AC:

430

AN:

251402

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.0210

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000744

AC:

1087

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

444

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0209

AC:

701

AN:

33476

American (AMR)

AF:

0.000939

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000160

AC:

178

AN:

1111996

Other (OTH)

AF:

0.00132

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00581

AC:

885

AN:

152224

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

411

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0194

AC:

806

AN:

41514

American (AMR)

AF:

0.00249

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68016

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00222

Hom.:

Bravo

AF:

0.00609

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00216

AC:

262

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr341Met in Exon 08 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 1.8% (66/3736) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs77321498). -

Jul 10, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TJP2-related disorder

Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.072

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

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

MetaRNN

Benign

0.0072

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.61

.;.;.;.;N;N;N;.;.;.;.;.;.;.

PhyloP100

1.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

.;N;.;.;.;N;N;.;.;.;N;.;N;.

REVEL

Benign

0.062

Sift

Uncertain

0.013

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

Sift4G

Benign

0.082

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

Polyphen

0.78, 0.18

.;.;.;.;P;B;P;.;.;.;.;.;.;.

Vest4

0.12, 0.13, 0.13, 0.19, 0.12

MVP

0.35

MPC

0.21

ClinPred

0.014

GERP RS

3.3

Varity_R

0.056

gMVP

0.26

Mutation Taster

=95/5

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