rs11788754

Positions:

• chr9-69246769-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004817.4(TJP2):​c.2646G>A​(p.Ala882=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.342

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 -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.2646G>A	p.Ala882=	synonymous_variant	18/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.2646G>A	p.Ala882=	synonymous_variant	18/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2018 AN: 152136 Hom.: 21 Cov.: 32

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

GnomAD3 exomes AF: 0.0141 AC: 3534 AN: 251458 Hom.: 36 AF XY: 0.0152 AC XY: 2066 AN XY: 135902

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 SAS exome AF: 0.0203

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

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.00724

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0133 AC: 2018 AN: 152254 Hom.: 21 Cov.: 32 AF XY: 0.0125 AC XY: 932 AN XY: 74438

Gnomad4 AFR AF: 0.00347

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0175 Hom.: 19

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
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	-0.38
CADD	Benign	7.1
DANN	Benign	0.60
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: rs11788754; hg19: chr9-71861685; COSMIC: COSV55266873;