chr9-69258846-A-C

Variant names:

• chr9-69258846-A-C
• rs2039785
• ENST00000650333.1:c.3338+5946A>C

Variant summary

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

The ENST00000650333.1(TJP2):​c.3338+5946A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 152,014 control chromosomes in the GnomAD database, including 18,985 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 0.50 (18985 hom., cov: 32)
• Consequence: TJP2 ENST00000650333.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400
• Publications: 3 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)

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 (SAS) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000650333.1	c.3338+5946A>C		intron_variant	Intron 22 of 22			ENSP00000496791.1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75461 AN: 151896 Hom.: 18964 Cov.: 32

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.497 AC: 75517 AN: 152014 Hom.: 18985 Cov.: 32 AF XY: 0.505 AC XY: 37547 AN XY: 74336

African (AFR) AF: 0.467 AC: 19375 AN: 41478

American (AMR) AF: 0.540 AC: 8249 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1649 AN: 3468

East Asian (EAS) AF: 0.609 AC: 3151 AN: 5170

South Asian (SAS) AF: 0.669 AC: 3228 AN: 4822

European-Finnish (FIN) AF: 0.568 AC: 5996 AN: 10554

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32190 AN: 67936

Other (OTH) AF: 0.477 AC: 1005 AN: 2106

Alfa AF: 0.480 Hom.: 26481

Bravo AF: 0.486

Asia WGS AF: 0.624 AC: 2171 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	2.5
DANN	Benign	0.65
PhyloP100		0.040

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2039785; hg19: chr9-71873762; COSMIC: COSV61960281;