rs864321697
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004817.4(TJP2):c.817delG(p.Ala273ProfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A273A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
TJP2
NM_004817.4 frameshift
NM_004817.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.116
Publications
7 publications found
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, 4Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- autosomal dominant nonsyndromic hearing lossInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
- familial hypercholanemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- nonsyndromic genetic hearing lossInheritance: AD Classification: LIMITED Submitted by: ClinGen
- hypercholanemia, familial 1Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-69221357-CG-C is Pathogenic according to our data. Variant chr9-69221357-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 219197.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004817.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TJP2 | NM_004817.4 | MANE Select | c.817delG | p.Ala273ProfsTer38 | frameshift | Exon 5 of 23 | NP_004808.2 | ||
| TJP2 | NM_001170416.2 | c.910delG | p.Ala304ProfsTer38 | frameshift | Exon 5 of 23 | NP_001163887.1 | |||
| TJP2 | NM_001369875.1 | c.829delG | p.Ala277ProfsTer38 | frameshift | Exon 5 of 23 | NP_001356804.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TJP2 | ENST00000377245.9 | TSL:1 MANE Select | c.817delG | p.Ala273ProfsTer38 | frameshift | Exon 5 of 23 | ENSP00000366453.4 | ||
| ENSG00000285130 | ENST00000642889.1 | c.1204delG | p.Ala402ProfsTer38 | frameshift | Exon 7 of 25 | ENSP00000493780.1 | |||
| TJP2 | ENST00000348208.9 | TSL:1 | c.817delG | p.Ala273ProfsTer38 | frameshift | Exon 5 of 21 | ENSP00000345893.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.00e-7 AC: 1AN: 1428446Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1AN XY: 707946 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1428446
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
707946
show subpopulations
African (AFR)
AF:
AC:
0
AN:
32810
American (AMR)
AF:
AC:
0
AN:
40004
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25460
East Asian (EAS)
AF:
AC:
0
AN:
37872
South Asian (SAS)
AF:
AC:
0
AN:
82774
European-Finnish (FIN)
AF:
AC:
0
AN:
49446
Middle Eastern (MID)
AF:
AC:
0
AN:
5718
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1095328
Other (OTH)
AF:
AC:
0
AN:
59034
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Cholestasis, progressive familial intrahepatic, 4 (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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