rs28556975

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004817.4(TJP2):c.2810T>C(p.Leu937Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,613,820 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 22 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 23 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.05

Publications

2 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=0.0074647665).

BP6

Variant 9-69248154-T-C is Benign according to our data. Variant chr9-69248154-T-C is described in ClinVar as Benign. ClinVar VariationId is 178680.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 = 0.00783 (1192/152228) while in subpopulation AFR AF = 0.0272 (1129/41522). AF 95% confidence interval is 0.0259. There are 22 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.2810T>C	p.Leu937Pro	missense_variant	Exon 19 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.2810T>C	p.Leu937Pro	missense_variant	Exon 19 of 23	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1 link	c.3197T>C	p.Leu1066Pro	missense_variant	Exon 21 of 25			ENSP00000493780.1

Frequencies

GnomAD3 genomes

AF:

0.00780

AC:

1186

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00219

AC:

546

AN:

249634

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.0309

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000844

AC:

1233

AN:

1461592

Hom.:

Cov.:

AF XY:

0.000697

AC XY:

507

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0311

AC:

1040

AN:

33470

American (AMR)

AF:

0.00148

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1111926

Other (OTH)

AF:

0.00151

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00783

AC:

1192

AN:

152228

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

576

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0272

AC:

1129

AN:

41522

American (AMR)

AF:

0.00327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68010

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

113

169

226

282

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:

0.00227

Hom.:

Bravo

AF:

0.00912

ESP6500AA

AF:

0.0284

AC:

125

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00272

AC:

330

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 23, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu937Pro in Exon 19E of TJP2: This variant is not expected to have clinical sig nificance because it has been identified in 2.8% (125/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs28556975). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0075

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

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.4

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

PhyloP100

5.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

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

REVEL

Benign

0.10

Sift

Benign

0.064

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

Sift4G

Benign

0.12

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

Polyphen

0.75, 0.59

.;.;.;P;P;P;.;.;.;.;.;.;.

Vest4

0.51, 0.54, 0.54, 0.51, 0.39

MVP

0.75

MPC

0.67

ClinPred

0.014

GERP RS

6.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.8

Varity_R

0.61

gMVP

0.41

Mutation Taster

=85/15

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