rs2095876

Positions:

• chr9-69248071-G-A
• chr9-69248071-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004817.4(TJP2):​c.2727G>A​(p.Ala909=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,750 control chromosomes in the GnomAD database, including 45,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4418 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41037 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.156

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=-0.27).
• BP6: Variant 9-69248071-G-A is Benign according to our data. Variant chr9-69248071-G-A is described in ClinVar as [Benign]. Clinvar id is 44106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.156 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.2727G>A	p.Ala909=	synonymous_variant	19/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.2727G>A	p.Ala909=	synonymous_variant	19/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34889 AN: 151964 Hom.: 4411 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.271 AC: 68033 AN: 251108 Hom.: 11523 AF XY: 0.258 AC XY: 34970 AN XY: 135746

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.435

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.226 AC: 330387 AN: 1461668 Hom.: 41037 Cov.: 37 AF XY: 0.224 AC XY: 162619 AN XY: 727120

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.230 AC: 34915 AN: 152082 Hom.: 4418 Cov.: 32 AF XY: 0.232 AC XY: 17261 AN XY: 74358

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.239

Alfa AF: 0.198 Hom.: 1989

Bravo AF: 0.244

Asia WGS AF: 0.310 AC: 1077 AN: 3478

EpiCase AF: 0.207

EpiControl AF: 0.207

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2016	- -
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	Nov 29, 2012	Ala909Ala in exon 19E 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 it has been identified in 21% (1812/8600) of European American chromosomes and 17% (755/4406) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/; dbSNP rs2095876) -

Cholestasis, progressive familial intrahepatic, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Hypercholanemia, familial 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs2095876; hg19: chr9-71862987; COSMIC: COSV55264507;