9-69220926-C-A

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.382C>A(p.Gln128Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,612,422 control chromosomes in the GnomAD database, including 4,544 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1987 hom., cov: 33)

Exomes 𝑓: 0.031 ( 2557 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.02

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041084588).

BP6

Variant 9-69220926-C-A is Benign according to our data. Variant chr9-69220926-C-A is described in ClinVar as Benign. ClinVar VariationId is 44100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.382C>A	p.Gln128Lys	missense_variant	Exon 5 of 23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9 link	c.382C>A	p.Gln128Lys	missense_variant	Exon 5 of 23	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1 link	c.769C>A	p.Gln257Lys	missense_variant	Exon 7 of 25			ENSP00000493780.1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15905

AN:

152190

Hom.:

1982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0578

Gnomad ASJ

AF:

0.0510

Gnomad EAS

AF:

0.0492

Gnomad SAS

AF:

0.0980

Gnomad FIN

AF:

0.0365

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0841

GnomAD2 exomes

AF:

0.0518

AC:

12984

AN:

250450

AF XY:

0.0497

show subpopulations

Gnomad AFR exome

AF:

0.310

Gnomad AMR exome

AF:

0.0303

Gnomad ASJ exome

AF:

0.0466

Gnomad EAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.0351

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0447

GnomAD4 exome

AF:

0.0306

AC:

44654

AN:

1460114

Hom.:

2557

Cov.:

AF XY:

0.0318

AC XY:

23113

AN XY:

726352

show subpopulations

African (AFR)

AF:

0.308

AC:

10303

AN:

33422

American (AMR)

AF:

0.0328

AC:

1465

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0453

AC:

1184

AN:

26128

East Asian (EAS)

AF:

0.0623

AC:

2475

AN:

39696

South Asian (SAS)

AF:

0.0923

AC:

7956

AN:

86160

European-Finnish (FIN)

AF:

0.0361

AC:

1927

AN:

53388

Middle Eastern (MID)

AF:

0.0737

AC:

326

AN:

4422

European-Non Finnish (NFE)

AF:

0.0145

AC:

16144

AN:

1111940

Other (OTH)

AF:

0.0477

AC:

2874

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

2617

5234

7851

10468

13085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.105

AC:

15937

AN:

152308

Hom.:

1987

Cov.:

AF XY:

0.105

AC XY:

7823

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.298

AC:

12388

AN:

41536

American (AMR)

AF:

0.0577

AC:

883

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0510

AC:

177

AN:

3472

East Asian (EAS)

AF:

0.0493

AC:

255

AN:

5174

South Asian (SAS)

AF:

0.0975

AC:

471

AN:

4832

European-Finnish (FIN)

AF:

0.0365

AC:

388

AN:

10628

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1122

AN:

68042

Other (OTH)

AF:

0.0833

AC:

176

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

608

1216

1824

2432

3040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<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:

0.0378

Hom.:

1160

Bravo

AF:

0.115

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.302

AC:

1328

ESP6500EA

AF:

0.0193

AC:

166

ExAC

AF:

0.0584

AC:

7087

Asia WGS

AF:

0.0820

AC:

283

AN:

3478

EpiCase

AF:

0.0199

EpiControl

AF:

0.0212

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gln105Lys in Exon 06 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 30.0% (1119/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41305539). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 03, 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

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0017

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

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.80

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

MetaRNN

Benign

0.0041

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

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

PhyloP100

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.35

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

REVEL

Benign

0.066

Sift

Benign

1.0

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

Sift4G

Benign

0.98

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

Polyphen

0.0010

.;.;.;.;.;.;B;B;B;.;.;.;.;.;.;.;.;.

Vest4

0.080, 0.078, 0.083, 0.13, 0.12

MPC

0.25

ClinPred

0.0022

GERP RS

2.9

Varity_R

0.063

gMVP

0.39

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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