9-69219464-G-A

Variant names:

• chr9-69219464-G-A
• rs11145746
• NM_004817.4:c.342+1105G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004817.4(TJP2):​c.342+1105G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,176 control chromosomes in the GnomAD database, including 2,735 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2735 hom., cov: 33)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.610
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4	c.342+1105G>A		intron_variant	Intron 4 of 22	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.342+1105G>A		intron_variant	Intron 4 of 22	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1	c.729+1105G>A		intron_variant	Intron 6 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28373 AN: 152058 Hom.: 2734 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.00809

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.186 AC: 28379 AN: 152176 Hom.: 2735 Cov.: 33 AF XY: 0.183 AC XY: 13599 AN XY: 74400

African (AFR) AF: 0.196 AC: 8139 AN: 41516

American (AMR) AF: 0.147 AC: 2245 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 716 AN: 3468

East Asian (EAS) AF: 0.00811 AC: 42 AN: 5178

South Asian (SAS) AF: 0.138 AC: 667 AN: 4822

European-Finnish (FIN) AF: 0.186 AC: 1968 AN: 10582

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13899 AN: 68000

Other (OTH) AF: 0.166 AC: 349 AN: 2108

Alfa AF: 0.187 Hom.: 502

Bravo AF: 0.185

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.9
DANN	Benign	0.74
PhyloP100		0.61
Mutation Taster		=100/0	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: rs11145746; hg19: chr9-71834380;