rs41277901

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004817.4(TJP2):c.1478G>A(p.Arg493Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00335 in 1,614,078 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 26 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 44 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.23

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020357668).

BP6

Variant 9-69229208-G-A is Benign according to our data. Variant chr9-69229208-G-A is described in ClinVar as [Benign]. Clinvar id is 44092.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 = 0.0122 (1856/152256) while in subpopulation AFR AF= 0.036 (1497/41536). AF 95% confidence interval is 0.0345. There are 26 homozygotes in gnomad4. There are 910 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4 linkuse as main transcript	c.1478G>A	p.Arg493Lys	missense_variant	10/23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9 linkuse as main transcript	c.1478G>A	p.Arg493Lys	missense_variant	10/23	1	NM_004817.4	ENSP00000366453	P2	Q9UDY2-1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1854

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0361

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00468

AC:

1177

AN:

251486

Hom.:

AF XY:

0.00394

AC XY:

535

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0372

Gnomad AMR exome

AF:

0.00714

Gnomad ASJ exome

AF:

0.00585

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00243

AC:

3547

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1645

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0384

Gnomad4 AMR exome

AF:

0.00778

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.0122

AC:

1856

AN:

152256

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

910

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0360

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00146

Gnomad4 OTH

AF:

0.0176

Alfa

AF:

0.00388

Hom.:

Bravo

AF:

0.0149

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0347

AC:

153

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00511

AC:

620

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg470Lys in Exon 11 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 3.6% (134/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs41277901). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2018	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.11

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

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

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

-1.0

MutationAssessor

Benign

1.3

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

MutationTaster

Benign

0.61

D;D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

0.0

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

REVEL

Benign

0.058

Sift

Benign

0.45

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

Sift4G

Benign

0.86

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

Polyphen

0.0070, 0.0040

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

Vest4

0.23, 0.25, 0.26, 0.24

MVP

0.40

MPC

0.20

ClinPred

0.010

GERP RS

4.0

Varity_R

0.075

gMVP

0.29

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