rs143965233

Positions:

• chr9-69251027-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004817.4(TJP2):​c.2992-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,862 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: TJP2 NM_004817.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002755
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.269

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-69251027-C-T is Benign according to our data. Variant chr9-69251027-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69251027-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.2992-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.2992-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 468 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00127 AC: 318 AN: 250104 Hom.: 0 AF XY: 0.00103 AC XY: 139 AN XY: 135428

Gnomad AFR exome AF: 0.00672

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00198 AC: 2891 AN: 1461544 Hom.: 3 Cov.: 32 AF XY: 0.00189 AC XY: 1372 AN XY: 727108

Gnomad4 AFR exome AF: 0.00627

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74488

Gnomad4 AFR AF: 0.00703

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00240 Hom.: 1

Bravo AF: 0.00309

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TJP2: BP4 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2013	2992-8C>T in intron 20A of TJP2: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (29/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/; dbSNP rs143965233). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2015	- -

Cholestasis, progressive familial intrahepatic, 4;C5542604:Hypercholanemia, familial 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.3
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs143965233; hg19: chr9-71865943;