rs199761505

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004817.4(TJP2):c.1258C>T(p.Arg420Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,613,784 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.39

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012251347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4 linkuse as main transcript	c.1258C>T	p.Arg420Cys	missense_variant	8/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9 linkuse as main transcript	c.1258C>T	p.Arg420Cys	missense_variant	8/23	1	NM_004817.4	P2	Q9UDY2-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000434

AC:

109

AN:

251344

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461568

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

213

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00188

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.0000630

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000342

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.000397

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 01, 2014

Variant classified as Uncertain Significance - Favor Benign. The Arg397Cys varia nt in TJP2 has not been previously reported in individuals with hearing loss, bu t has been identified in 0.04% (3/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs19976 1505). Arg397 is not conserved in mammals and across evolutionary distant specie s, supporting that a change at this position may be tolerated. Additional comput ational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the conservation data, we would le an towards a more likely benign role. -

Cholestasis, progressive familial intrahepatic, 4;C5542604:Hypercholanemia, familial 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

TJP2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2024

This variant is classified as likely 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.039

MetaRNN

Benign

0.012

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

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.40

Polyphen

1.0, 0.99

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

Vest4

0.54, 0.56, 0.50, 0.49, 0.63

MVP

0.64

MPC

0.85

ClinPred

0.11

GERP RS

4.9

Varity_R

0.16

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over