rs34774441

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004817.4(TJP2):c.2004G>A(p.Met668Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0592 in 1,614,088 control chromosomes in the GnomAD database, including 3,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.047 ( 201 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3021 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.96

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:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020027757).

BP6

Variant 9-69236961-G-A is Benign according to our data. Variant chr9-69236961-G-A is described in ClinVar as [Benign]. Clinvar id is 44095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4 linkuse as main transcript	c.2004G>A	p.Met668Ile	missense_variant	14/23	ENST00000377245.9	NP_004808.2	Q9UDY2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9 linkuse as main transcript	c.2004G>A	p.Met668Ile	missense_variant	14/23	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 linkuse as main transcript	c.2391G>A	p.Met797Ile	missense_variant	16/25			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

AF:

0.0470

AC:

7156

AN:

152176

Hom.:

201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0199

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0423

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0788

Gnomad FIN

AF:

0.0404

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0622

Gnomad OTH

AF:

0.0626

GnomAD3 exomes

AF:

0.0539

AC:

13560

AN:

251450

Hom.:

483

AF XY:

0.0577

AC XY:

7842

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0211

Gnomad AMR exome

AF:

0.0289

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0845

Gnomad FIN exome

AF:

0.0377

Gnomad NFE exome

AF:

0.0629

Gnomad OTH exome

AF:

0.0609

GnomAD4 exome

AF:

0.0605

AC:

88456

AN:

1461794

Hom.:

3021

Cov.:

AF XY:

0.0620

AC XY:

45090

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0221

Gnomad4 AMR exome

AF:

0.0306

Gnomad4 ASJ exome

AF:

0.124

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0844

Gnomad4 FIN exome

AF:

0.0434

Gnomad4 NFE exome

AF:

0.0621

Gnomad4 OTH exome

AF:

0.0626

GnomAD4 genome

AF:

0.0470

AC:

7157

AN:

152294

Hom.:

201

Cov.:

AF XY:

0.0452

AC XY:

3368

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0199

Gnomad4 AMR

AF:

0.0423

Gnomad4 ASJ

AF:

0.131

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0791

Gnomad4 FIN

AF:

0.0404

Gnomad4 NFE

AF:

0.0622

Gnomad4 OTH

AF:

0.0614

Alfa

AF:

0.0617

Hom.:

508

Bravo

AF:

0.0454

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0612

AC:

236

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.0649

AC:

558

ExAC

AF:

0.0552

AC:

6700

Asia WGS

AF:

0.0350

AC:

122

AN:

3478

EpiCase

AF:

0.0655

EpiControl

AF:

0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Met645Ile in Exon 15 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 6.5% (458/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs34774441). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.97

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

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.19

Sift

Uncertain

0.011

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.64, 0.40

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

Vest4

0.57, 0.50, 0.57, 0.61, 0.61

MutPred

0.31

.;.;.;.;Loss of disorder (P = 0.1156);Loss of disorder (P = 0.1156);Loss of disorder (P = 0.1156);Loss of disorder (P = 0.1156);Loss of disorder (P = 0.1156);.;.;.;.;.;

MPC

0.65

ClinPred

0.026

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.54

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