rs727504461
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_004817.4(TJP2):โc.1213_1215delโ(p.Ile405del) variant causes a inframe deletion, splice region change. The variant allele was found at a frequency of 0.000211 in 1,580,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: ๐ 0.00030 ( 0 hom., cov: 32)
Exomes ๐: 0.00020 ( 0 hom. )
Consequence
TJP2
NM_004817.4 inframe_deletion, splice_region
NM_004817.4 inframe_deletion, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.13
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_004817.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TJP2 | NM_004817.4 | c.1213_1215del | p.Ile405del | inframe_deletion, splice_region_variant | 8/23 | ENST00000377245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TJP2 | ENST00000377245.9 | c.1213_1215del | p.Ile405del | inframe_deletion, splice_region_variant | 8/23 | 1 | NM_004817.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000360 AC: 90AN: 249774Hom.: 0 AF XY: 0.000355 AC XY: 48AN XY: 135338
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GnomAD4 exome AF: 0.000202 AC: 288AN: 1427824Hom.: 0 AF XY: 0.000209 AC XY: 149AN XY: 712360
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GnomAD4 genome AF: 0.000296 AC: 45AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 05, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 08, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Ile382del varia nt in TJP2 has not been reported in affected individuals, but has been identifie d in 0.07% (6/8254) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs2 01033926). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. This variant causes a n in-frame deletion of a single amino acid isoleucine (Ile)] at position 382 tha t is not highly conserved in mammals and across evolutionarily distant species. In summary, the clinical significance of this variant cannot be determined with certainty; however, based upon its presence in the general population and the la ck of conservation at the amino acid position, we lean towards a more likely ben ign role. - |
Nonsyndromic Hearing Loss, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cholestasis, progressive familial intrahepatic, 4;C5542604:Hypercholanemia, familial 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 15, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at