rs17062695

Positions:

• chr9-69226102-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004817.4(TJP2):​c.1137A>G​(p.Leu379=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 1,614,094 control chromosomes in the GnomAD database, including 4,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (653 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3371 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.58

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=-0.78).
• BP6: Variant 9-69226102-A-G is Benign according to our data. Variant chr9-69226102-A-G is described in ClinVar as [Benign]. Clinvar id is 44090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.1137A>G	p.Leu379=	synonymous_variant	7/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.1137A>G	p.Leu379=	synonymous_variant	7/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12729 AN: 152162 Hom.: 652 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.0982

Gnomad SAS AF: 0.0839

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.0865

GnomAD3 exomes AF: 0.0683 AC: 17182 AN: 251394 Hom.: 688 AF XY: 0.0673 AC XY: 9149 AN XY: 135878

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0816

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0647 AC: 94547 AN: 1461814 Hom.: 3371 Cov.: 32 AF XY: 0.0647 AC XY: 47021 AN XY: 727204

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0808

Gnomad4 ASJ exome AF: 0.0515

Gnomad4 EAS exome AF: 0.0864

Gnomad4 SAS exome AF: 0.0812

Gnomad4 FIN exome AF: 0.0210

Gnomad4 NFE exome AF: 0.0615

Gnomad4 OTH exome AF: 0.0709

GnomAD4 genome AF: 0.0837 AC: 12743 AN: 152280 Hom.: 653 Cov.: 33 AF XY: 0.0825 AC XY: 6143 AN XY: 74466

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0947

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.0983

Gnomad4 SAS AF: 0.0835

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.0563

Gnomad4 OTH AF: 0.0880

Alfa AF: 0.0666 Hom.: 463

Bravo AF: 0.0934

Asia WGS AF: 0.100 AC: 348 AN: 3478

EpiCase AF: 0.0592

EpiControl AF: 0.0610

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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	Leu356Leu in Exon 08 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 14.1% (528/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs17062695). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.45
DANN	Benign	0.65

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: rs17062695; hg19: chr9-71841018; COSMIC: COSV55267424;