rs113137067

Variant names:

• chr9-69173991-G-A
• rs113137067
• ENST00000642889.1:c.447+22220G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001369871.1(TJP2):​c.-127-11096G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 985,062 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (33 hom.)
• Consequence: TJP2 NM_001369871.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.39
• Publications: 2 publications found

Genes affected

ENSG00000285130 (HGNC:):

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: Orphanet, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-69173991-G-A is Benign according to our data. Variant chr9-69173991-G-A is described in ClinVar as Benign. ClinVar VariationId is 1280535.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369871.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	NM_001369871.1		c.-127-11096G>A		intron	N/A	NP_001356800.1	Q9UDY2-3
	TJP2	NM_001369870.1		c.-10+22220G>A		intron	N/A	NP_001356799.1
	TJP2	NM_001170414.2		c.-10+22220G>A		intron	N/A	NP_001163885.1	B7Z2R3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285130	ENST00000642889.1		c.447+22220G>A		intron	N/A	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000636438.1	TSL:5	c.237+22220G>A		intron	N/A	ENSP00000489860.1	A0A1B0GTW1
	TJP2	ENST00000647986.1		c.-127-11096G>A		intron	N/A	ENSP00000496877.1	A0A3B3IRV6

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2533 AN: 151850 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00137 AC: 1145 AN: 833102 Hom.: 33 AF XY: 0.00125 AC XY: 481 AN XY: 384708

African (AFR) AF: 0.0616 AC: 973 AN: 15786

American (AMR) AF: 0.00407 AC: 4 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5152

East Asian (EAS) AF: 0.000275 AC: 1 AN: 3630

South Asian (SAS) AF: 0.000122 AC: 2 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 276

Middle Eastern (MID) AF: 0.00185 AC: 3 AN: 1620

European-Non Finnish (NFE) AF: 0.0000866 AC: 66 AN: 761896

Other (OTH) AF: 0.00352 AC: 96 AN: 27298

GnomAD4 genome AF: 0.0167 AC: 2535 AN: 151960 Hom.: 61 Cov.: 32 AF XY: 0.0162 AC XY: 1200 AN XY: 74278

African (AFR) AF: 0.0580 AC: 2405 AN: 41450

American (AMR) AF: 0.00661 AC: 101 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67918

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0140 Hom.: 3

Bravo AF: 0.0187

Asia WGS AF: 0.00347 AC: 12 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.78
PhyloP100		1.4
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs113137067; hg19: chr9-71788907;