NM_004817.4:c.2646G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004817.4(TJP2):​c.2646G>A​(p.Ala882Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,614,012 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 32)
Exomes 𝑓: 0.018 ( 283 hom. )

Consequence

TJP2
NM_004817.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.342

Publications

5 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 9-69246769-G-A is Benign according to our data. Variant chr9-69246769-G-A is described in ClinVar as [Benign]. Clinvar id is 44098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.342 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2018/152254) while in subpopulation NFE AF = 0.0212 (1439/68030). AF 95% confidence interval is 0.0202. There are 21 homozygotes in GnomAd4. There are 932 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 21 AD,Unknown,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TJP2NM_004817.4 linkc.2646G>A p.Ala882Ala synonymous_variant Exon 18 of 23 ENST00000377245.9 NP_004808.2 Q9UDY2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TJP2ENST00000377245.9 linkc.2646G>A p.Ala882Ala synonymous_variant Exon 18 of 23 1 NM_004817.4 ENSP00000366453.4 Q9UDY2-1
ENSG00000285130ENST00000642889.1 linkc.3033G>A p.Ala1011Ala synonymous_variant Exon 20 of 25 ENSP00000493780.1 A0A2R8YDH4

Frequencies

GnomAD3 genomes
AF:
0.0133
AC:
2018
AN:
152136
Hom.:
21
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00348
Gnomad AMI
AF:
0.00879
Gnomad AMR
AF:
0.0147
Gnomad ASJ
AF:
0.0161
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.0184
Gnomad FIN
AF:
0.00217
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0211
Gnomad OTH
AF:
0.0124
GnomAD2 exomes
AF:
0.0141
AC:
3534
AN:
251458
AF XY:
0.0152
show subpopulations
Gnomad AFR exome
AF:
0.00302
Gnomad AMR exome
AF:
0.00726
Gnomad ASJ exome
AF:
0.0150
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00240
Gnomad NFE exome
AF:
0.0203
Gnomad OTH exome
AF:
0.0164
GnomAD4 exome
AF:
0.0180
AC:
26248
AN:
1461758
Hom.:
283
Cov.:
31
AF XY:
0.0181
AC XY:
13170
AN XY:
727186
show subpopulations
African (AFR)
AF:
0.00367
AC:
123
AN:
33478
American (AMR)
AF:
0.00724
AC:
324
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0135
AC:
353
AN:
26128
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39692
South Asian (SAS)
AF:
0.0192
AC:
1652
AN:
86258
European-Finnish (FIN)
AF:
0.00322
AC:
172
AN:
53418
Middle Eastern (MID)
AF:
0.0248
AC:
143
AN:
5768
European-Non Finnish (NFE)
AF:
0.0203
AC:
22586
AN:
1111900
Other (OTH)
AF:
0.0148
AC:
894
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1357
2713
4070
5426
6783
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
836
1672
2508
3344
4180
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0133
AC:
2018
AN:
152254
Hom.:
21
Cov.:
32
AF XY:
0.0125
AC XY:
932
AN XY:
74438
show subpopulations
African (AFR)
AF:
0.00347
AC:
144
AN:
41542
American (AMR)
AF:
0.0147
AC:
224
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.0161
AC:
56
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5176
South Asian (SAS)
AF:
0.0182
AC:
88
AN:
4822
European-Finnish (FIN)
AF:
0.00217
AC:
23
AN:
10610
Middle Eastern (MID)
AF:
0.0306
AC:
9
AN:
294
European-Non Finnish (NFE)
AF:
0.0212
AC:
1439
AN:
68030
Other (OTH)
AF:
0.0123
AC:
26
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.512
Heterozygous variant carriers
0
115
230
345
460
575
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
26
52
78
104
130
<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:
0.0174
Hom.:
23
Bravo
AF:
0.0132
Asia WGS
AF:
0.00577
AC:
20
AN:
3478
EpiCase
AF:
0.0221
EpiControl
AF:
0.0229

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Nov 19, 2018
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 07, 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:2
May 07, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Ala859Ala in Exon 19 of TJP2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 2.1% (145/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs11788754). -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
CADD
Benign
7.1
DANN
Benign
0.60
PhyloP100
-0.34
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=99/1
polymorphism (auto)

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

Other links and lift over

dbSNP: rs11788754; hg19: chr9-71861685; COSMIC: COSV55266873; API