rs2498423

Variant names:

• chr9-69245356-A-G
• rs2498423
• NM_004817.4:c.2567-1334A>G

Variant summary

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

The NM_004817.4(TJP2):​c.2567-1334A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 152,118 control chromosomes in the GnomAD database, including 33,464 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 0.66 (33464 hom., cov: 32)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4	c.2567-1334A>G		intron_variant	Intron 17 of 22	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.2567-1334A>G		intron_variant	Intron 17 of 22	1	NM_004817.4	ENSP00000366453.4
ENSG00000285130	ENST00000642889.1	c.2954-1334A>G		intron_variant	Intron 19 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100741 AN: 152000 Hom.: 33426 Cov.: 32

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.632

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

GnomAD4 genome AF: 0.663 AC: 100830 AN: 152118 Hom.: 33464 Cov.: 32 AF XY: 0.668 AC XY: 49635 AN XY: 74346

African (AFR) AF: 0.691 AC: 28680 AN: 41506

American (AMR) AF: 0.695 AC: 10615 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3336 AN: 5168

South Asian (SAS) AF: 0.683 AC: 3287 AN: 4816

European-Finnish (FIN) AF: 0.716 AC: 7572 AN: 10580

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42944 AN: 67978

Other (OTH) AF: 0.636 AC: 1342 AN: 2110

Alfa AF: 0.661 Hom.: 4923

Bravo AF: 0.660

Asia WGS AF: 0.673 AC: 2340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.67
DANN	Benign	0.79
PhyloP100		-0.97
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: rs2498423; hg19: chr9-71860272;