rs111595785

chr9-69254296-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004817.4(TJP2):c.3495G>A(p.Glu1165=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,614,244 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (36 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.689

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-69254296-G-A is Benign according to our data. Variant chr9-69254296-G-A is described in ClinVar as [Benign]. Clinvar id is 44099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69254296-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.689 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00475 (6937/1461892) while in subpopulation AFR AF= 0.0188 (629/33480). AF 95% confidence interval is 0.0176. There are 36 homozygotes in gnomad4_exome. There are 3432 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.3495G>A	p.Glu1165=	synonymous_variant	23/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.3495G>A	p.Glu1165=	synonymous_variant	23/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1205 AN: 152234 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00575

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00542

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00504 AC: 1267 AN: 251476 Hom.: 8 AF XY: 0.00483 AC XY: 656 AN XY: 135906

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.00490

Gnomad OTH exome AF: 0.00651

GnomAD4 exome AF: 0.00475 AC: 6937 AN: 1461892 Hom.: 36 Cov.: 30 AF XY: 0.00472 AC XY: 3432 AN XY: 727246

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00461

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.00795 AC: 1211 AN: 152352 Hom.: 10 Cov.: 33 AF XY: 0.00762 AC XY: 568 AN XY: 74506

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00542

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00661 Hom.: 0

Bravo AF: 0.00793

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00640

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Glu995Glu in Exon 22 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 1.4% (54/3738) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs111595785). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.39
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs111595785; hg19: chr9-71869212;