9-69226102-A-G

Variant names:

• chr9-69226102-A-G
• rs17062695
• NM_004817.4:c.1137A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004817.4(TJP2):​c.1137A>G​(p.Leu379Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 1,614,094 control chromosomes in the GnomAD database, including 4,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (653 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3371 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.58
• Publications: 14 publications found

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]

TJP2 Gene-Disease associations (from GenCC):

• cholestasis, progressive familial intrahepatic, 4

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
• familial hypercholanemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypercholanemia, familial 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-69226102-A-G is Benign according to our data. Variant chr9-69226102-A-G is described in ClinVar as Benign. ClinVar VariationId is 44090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004817.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	NM_004817.4	MANE Select	c.1137A>G	p.Leu379Leu	synonymous	Exon 7 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.1230A>G	p.Leu410Leu	synonymous	Exon 7 of 23	NP_001163887.1
	TJP2	NM_001369875.1		c.1149A>G	p.Leu383Leu	synonymous	Exon 7 of 23	NP_001356804.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	ENST00000377245.9	TSL:1 MANE Select	c.1137A>G	p.Leu379Leu	synonymous	Exon 7 of 23	ENSP00000366453.4
	ENSG00000285130	ENST00000642889.1		c.1524A>G	p.Leu508Leu	synonymous	Exon 9 of 25	ENSP00000493780.1
	TJP2	ENST00000348208.9	TSL:1	c.1137A>G	p.Leu379Leu	synonymous	Exon 7 of 21	ENSP00000345893.4

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12729 AN: 152162 Hom.: 652 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.0982

Gnomad SAS AF: 0.0839

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0563

Gnomad OTH AF: 0.0865

GnomAD2 exomes AF: 0.0683 AC: 17182 AN: 251394 AF XY: 0.0673

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0688

GnomAD4 exome AF: 0.0647 AC: 94547 AN: 1461814 Hom.: 3371 Cov.: 32 AF XY: 0.0647 AC XY: 47021 AN XY: 727204

African (AFR) AF: 0.150 AC: 5014 AN: 33476

American (AMR) AF: 0.0808 AC: 3613 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0515 AC: 1346 AN: 26132

East Asian (EAS) AF: 0.0864 AC: 3428 AN: 39690

South Asian (SAS) AF: 0.0812 AC: 7000 AN: 86252

European-Finnish (FIN) AF: 0.0210 AC: 1121 AN: 53408

Middle Eastern (MID) AF: 0.0657 AC: 379 AN: 5768

European-Non Finnish (NFE) AF: 0.0615 AC: 68363 AN: 1111978

Other (OTH) AF: 0.0709 AC: 4283 AN: 60388

GnomAD4 genome AF: 0.0837 AC: 12743 AN: 152280 Hom.: 653 Cov.: 33 AF XY: 0.0825 AC XY: 6143 AN XY: 74466

African (AFR) AF: 0.142 AC: 5898 AN: 41518

American (AMR) AF: 0.0947 AC: 1450 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.0983 AC: 510 AN: 5190

South Asian (SAS) AF: 0.0835 AC: 403 AN: 4826

European-Finnish (FIN) AF: 0.0169 AC: 180 AN: 10624

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0563 AC: 3828 AN: 68026

Other (OTH) AF: 0.0880 AC: 186 AN: 2114

Alfa AF: 0.0704 Hom.: 728

Bravo AF: 0.0934

Asia WGS AF: 0.100 AC: 348 AN: 3478

EpiCase AF: 0.0592

EpiControl AF: 0.0610

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu356Leu in Exon 08 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 14.1% (528/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs17062695).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.45
DANN	Benign	0.65
PhyloP100		-3.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17062695; hg19: chr9-71841018; COSMIC: COSV55267424;