Genetic Variant TJP2:c.60+9625A>G (chr9-69184057-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004817.4(TJP2):c.60+9625A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 152,242 control chromosomes in the GnomAD database, including 62,440 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.91 ( 62440 hom., cov: 32)

Consequence

TJP2
NM_004817.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.295

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.60+9625A>G		intron_variant	Intron 1 of 22	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9 link	c.60+9625A>G		intron_variant	Intron 1 of 22	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1 link	c.448-28491A>G		intron_variant	Intron 3 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes

AF:

0.905

AC:

137699

AN:

152124

Hom.:

62400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.863

Gnomad AMI

AF:

0.900

Gnomad AMR

AF:

0.897

Gnomad ASJ

AF:

0.924

Gnomad EAS

AF:

0.934

Gnomad SAS

AF:

0.916

Gnomad FIN

AF:

0.946

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.898

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.905

AC:

137795

AN:

152242

Hom.:

62440

Cov.:

AF XY:

0.907

AC XY:

67547

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.863

AC:

35839

AN:

41520

American (AMR)

AF:

0.897

AC:

13715

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.924

AC:

3206

AN:

3470

East Asian (EAS)

AF:

0.934

AC:

4844

AN:

5186

South Asian (SAS)

AF:

0.917

AC:

4420

AN:

4822

European-Finnish (FIN)

AF:

0.946

AC:

10039

AN:

10614

Middle Eastern (MID)

AF:

0.949

AC:

277

AN:

292

European-Non Finnish (NFE)

AF:

0.922

AC:

62742

AN:

68028

Other (OTH)

AF:

0.898

AC:

1894

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

673

1346

2018

2691

3364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.917

Hom.:

64482

Bravo

AF:

0.899

Asia WGS

AF:

0.904

AC:

3144

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.7

(source)

DANN

Benign

0.28

PhyloP100

-0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over