rs4493966

Positions:

• chr9-69205232-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004817.4(TJP2):​c.61-7316G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 1,537,142 control chromosomes in the GnomAD database, including 2,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (347 hom., cov: 33)
  • Exomes 𝑓: 0.043 (2178 hom.)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.142

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.739829E-4).
• BP6: Variant 9-69205232-G-A is Benign according to our data. Variant chr9-69205232-G-A is described in ClinVar as [Benign]. Clinvar id is 44104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.61-7316G>A		intron_variant		ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.61-7316G>A		intron_variant		1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6639 AN: 152174 Hom.: 340 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.0541

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0574

GnomAD3 exomes AF: 0.0738 AC: 10289 AN: 139454 Hom.: 914 AF XY: 0.0665 AC XY: 4975 AN XY: 74796

Gnomad AFR exome AF: 0.00895

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.0358

Gnomad EAS exome AF: 0.0492

Gnomad SAS exome AF: 0.0405

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0597

GnomAD4 exome AF: 0.0428 AC: 59259 AN: 1384850 Hom.: 2178 Cov.: 33 AF XY: 0.0423 AC XY: 28896 AN XY: 683356

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.0336

Gnomad4 EAS exome AF: 0.0439

Gnomad4 SAS exome AF: 0.0403

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0382

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0437 AC: 6651 AN: 152292 Hom.: 347 Cov.: 33 AF XY: 0.0449 AC XY: 3344 AN XY: 74466

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.0535

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0400 Hom.: 191

Bravo AF: 0.0553

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.0166 AC: 23

ESP6500EA AF: 0.0371 AC: 118

ExAC AF: 0.0330 AC: 708

Asia WGS AF: 0.0560 AC: 194 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2013	Arg24His in Exon 01D of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 3.7% (118/3182) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs4493966). -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.80
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.22	T;T;T;T
MetaRNN	Benign	0.00087	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.72	N;.;N;.
REVEL	Benign	0.028
Sift	Benign	0.29	T;.;T;.
Sift4G	Benign	0.24	T;.;T;.
Vest4		0.10
MPC		0.24
ClinPred		0.0013	T
GERP RS		-2.6
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4493966; hg19: chr9-71820148; COSMIC: COSV55264360;