rs150883816

Positions:

• chr9-69221242-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004817.4(TJP2):​c.698G>A​(p.Arg233Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,607,412 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R233R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.89

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00434345).
• BP6: Variant 9-69221242-G-A is Benign according to our data. Variant chr9-69221242-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.698G>A	p.Arg233Gln	missense_variant	5/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.698G>A	p.Arg233Gln	missense_variant	5/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000463 AC: 107 AN: 231248 Hom.: 1 AF XY: 0.000316 AC XY: 40 AN XY: 126482

Gnomad AFR exome AF: 0.00681

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000340

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000196

Gnomad OTH exome AF: 0.000353

GnomAD4 exome AF: 0.000180 AC: 262 AN: 1455224 Hom.: 2 Cov.: 33 AF XY: 0.000147 AC XY: 106 AN XY: 723524

Gnomad4 AFR exome AF: 0.00633

Gnomad4 AMR exome AF: 0.000249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000400

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74404

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000559 Hom.: 1

Bravo AF: 0.00200

ESP6500AA AF: 0.00573 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000573 AC: 69

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg210Gln in Exon 06 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (15/3710) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs150883816). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.19	.;.;.;.;T;.;T;.;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T;T;T;T;.;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.30	.;.;.;.;N;N;N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.72	.;N;.;.;.;N;N;.;.;.;N;.;N;.
REVEL	Benign	0.037
Sift	Benign	0.11	.;T;.;.;.;T;T;.;.;.;T;.;T;.
Sift4G	Benign	0.086	.;T;.;.;.;T;T;.;.;.;T;.;T;.
Polyphen		0.0, 0.99	.;.;.;.;B;D;B;.;.;.;.;.;.;.
Vest4		0.32, 0.33, 0.33, 0.34, 0.32
MVP		0.53
MPC		0.22
ClinPred		0.0028	T
GERP RS		0.53
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.023
gMVP		0.45

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: rs150883816; hg19: chr9-71836158;