rs201977617

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_004817.4(TJP2):c.644G>A(p.Arg215His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,599,618 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R215C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 6 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.36

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005293697).

BP6

Variant 9-69221188-G-A is Benign according to our data. Variant chr9-69221188-G-A is described in ClinVar as Benign. ClinVar VariationId is 178542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 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.644G>A	p.Arg215His	missense_variant	Exon 5 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.644G>A	p.Arg215His	missense_variant	Exon 5 of 23	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 link	c.1031G>A	p.Arg344His	missense_variant	Exon 7 of 25			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

AF:

0.00301

AC:

458

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000811

AC:

176

AN:

217006

AF XY:

0.000614

show subpopulations

Gnomad AFR exome

AF:

0.0128

Gnomad AMR exome

AF:

0.000429

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000185

GnomAD4 exome

AF:

0.000321

AC:

464

AN:

1447356

Hom.:

Cov.:

AF XY:

0.000302

AC XY:

217

AN XY:

719098

show subpopulations

African (AFR)

AF:

0.0116

AC:

385

AN:

33178

American (AMR)

AF:

0.000552

AC:

AN:

43468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25836

East Asian (EAS)

AF:

0.00

AC:

AN:

39052

South Asian (SAS)

AF:

0.00

AC:

AN:

84550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50670

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000362

AC:

AN:

1105118

Other (OTH)

AF:

0.000804

AC:

AN:

59738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00300

AC:

457

AN:

152262

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0107

AC:

445

AN:

41550

American (AMR)

AF:

0.000457

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68000

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

109

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:

0.00108

Hom.:

Bravo

AF:

0.00370

ESP6500AA

AF:

0.00815

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00105

AC:

124

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 25, 2020

GeneDx

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

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg192His in Exon 06 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 0.8% (28/3624) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). -

Mar 18, 2016

Eurofins Ntd Llc (ga)

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

0.097

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.96

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

MetaRNN

Benign

0.0053

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

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

.;.;.;.;M;M;M;.;.;.;.;.;.;.

PhyloP100

3.4

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.88

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

REVEL

Benign

0.075

Sift

Benign

0.25

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

Sift4G

Uncertain

0.025

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

Polyphen

0.028, 0.017

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

Vest4

0.34, 0.42, 0.33, 0.40, 0.34

MVP

0.70

MPC

0.25

ClinPred

0.0066

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.60

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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