9-69248319-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The ENST00000636247.1(TJP2):n.3054A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,484,356 control chromosomes in the GnomAD database, including 4,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.071 ( 432 hom., cov: 32)

Exomes 𝑓: 0.079 ( 4367 hom. )

Consequence

TJP2
ENST00000636247.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.522

Publications

8 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.018).

BP6

Variant 9-69248319-A-G is Benign according to our data. Variant chr9-69248319-A-G is described in ClinVar as [Benign]. Clinvar id is 44109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.2880+95A>G		intron_variant	Intron 19 of 22	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.2880+95A>G		intron_variant	Intron 19 of 22	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 link	c.3267+95A>G		intron_variant	Intron 21 of 24			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

AF:

0.0711

AC:

10824

AN:

152130

Hom.:

430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0559

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0600

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.00598

Gnomad SAS

AF:

0.0854

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0828

Gnomad OTH

AF:

0.0771

GnomAD2 exomes

AF:

0.0661

AC:

6723

AN:

101664

AF XY:

0.0687

show subpopulations

Gnomad AFR exome

AF:

0.0522

Gnomad AMR exome

AF:

0.0421

Gnomad ASJ exome

AF:

0.0601

Gnomad EAS exome

AF:

0.00651

Gnomad FIN exome

AF:

0.0900

Gnomad NFE exome

AF:

0.0817

Gnomad OTH exome

AF:

0.0642

GnomAD4 exome

AF:

0.0786

AC:

104690

AN:

1332108

Hom.:

4367

Cov.:

AF XY:

0.0791

AC XY:

51273

AN XY:

648358

show subpopulations

African (AFR)

AF:

0.0558

AC:

1658

AN:

29688

American (AMR)

AF:

0.0424

AC:

1155

AN:

27266

Ashkenazi Jewish (ASJ)

AF:

0.0590

AC:

1217

AN:

20628

East Asian (EAS)

AF:

0.00299

AC:

105

AN:

35090

South Asian (SAS)

AF:

0.0884

AC:

5994

AN:

67784

European-Finnish (FIN)

AF:

0.0929

AC:

4351

AN:

46820

Middle Eastern (MID)

AF:

0.0828

AC:

444

AN:

5364

European-Non Finnish (NFE)

AF:

0.0820

AC:

85662

AN:

1044482

Other (OTH)

AF:

0.0746

AC:

4104

AN:

54986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

5450

10900

16350

21800

27250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0712

AC:

10837

AN:

152248

Hom.:

432

Cov.:

AF XY:

0.0719

AC XY:

5350

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0560

AC:

2328

AN:

41558

American (AMR)

AF:

0.0599

AC:

915

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0562

AC:

195

AN:

3472

East Asian (EAS)

AF:

0.00580

AC:

AN:

5172

South Asian (SAS)

AF:

0.0855

AC:

412

AN:

4818

European-Finnish (FIN)

AF:

0.103

AC:

1089

AN:

10610

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0828

AC:

5632

AN:

68018

Other (OTH)

AF:

0.0768

AC:

162

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

517

1033

1550

2066

2583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0745

Hom.:

1497

Bravo

AF:

0.0669

Asia WGS

AF:

0.0430

AC:

151

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 21, 2018

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

- -

not specified

Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

His992Arg in Exon 19 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 6.9% (174/2532) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs77236826). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.42

(source)

DANN

Benign

0.23

PhyloP100

-0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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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9-69248319-A-G

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