rs374523970

Positions:

• chr9-69221462-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The ENST00000377245.9(TJP2):​c.918C>T​(p.Ile306=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,598,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: TJP2 ENST00000377245.9 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0230

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 9-69221462-C-T is Benign according to our data. Variant chr9-69221462-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44102.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}. Variant chr9-69221462-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.023 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4	c.918C>T	p.Ile306=	synonymous_variant	5/23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.918C>T	p.Ile306=	synonymous_variant	5/23	1	NM_004817.4	ENSP00000366453	P2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000388 AC: 82 AN: 211578 Hom.: 0 AF XY: 0.000362 AC XY: 42 AN XY: 116112

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.000282

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.000568

GnomAD4 exome AF: 0.000680 AC: 984 AN: 1446108 Hom.: 0 Cov.: 33 AF XY: 0.000639 AC XY: 459 AN XY: 717906

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000828

Gnomad4 OTH exome AF: 0.000787

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74492

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000629 Hom.: 0

Bravo AF: 0.000457

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TJP2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ile283Ile in Exon 06 of TJP2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.1% (2/3506) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.7
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374523970; hg19: chr9-71836378;