rs200384355

Positions:

• chr9-69248243-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004817.4(TJP2):​c.2880+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,570,086 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -5.49

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]

ENSG00000285130 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-69248243-C-T is Benign according to our data. Variant chr9-69248243-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165422.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4	c.2880+19C>T		intron_variant		ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.2880+19C>T		intron_variant		1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1	c.3267+19C>T		intron_variant				ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000438 AC: 78 AN: 178100 Hom.: 0 AF XY: 0.000462 AC XY: 44 AN XY: 95314

Gnomad AFR exome AF: 0.0000947

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.000116

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.000308 AC: 436 AN: 1417784 Hom.: 2 Cov.: 32 AF XY: 0.000331 AC XY: 232 AN XY: 701568

Gnomad4 AFR exome AF: 0.000186

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.0000971

Gnomad4 FIN exome AF: 0.0000789

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000835

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74462

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000417 Hom.: 0

Bravo AF: 0.000544

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 25, 2015

p.Arg967Trp in exon 19 in TJP2: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (4/1478) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs200384355). In addition, the variant occurs in a region that is poorly cons erved across species and lies in an intron in several transcript isoforms of TJP 2. Furthermore, this variant has been identified by our laboratory in 1 individu al with hearing loss who was homozygous for a pathogenic variant in another gene that explained their disease, and therefore its co-occurence with another disea se-causing variant suggests an unlikely role for this variant in that individual 's hearing loss. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.7
DANN	Uncertain	0.99
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: rs200384355; hg19: chr9-71863159;