NM_004817.4:c.2275+16T>G

Variant names:

• chr9-69237989-T-G
• rs73450890
• NM_004817.4:c.2275+16T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004817.4(TJP2):​c.2275+16T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 1,566,400 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (333 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (312 hom.)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.709
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 9-69237989-T-G is Benign according to our data. Variant chr9-69237989-T-G is described in ClinVar as Benign. ClinVar VariationId is 259552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 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.2275+16T>G		intron	N/A	NP_004808.2
	TJP2	NM_001170416.2		c.2368+16T>G		intron	N/A	NP_001163887.1
	TJP2	NM_001369875.1		c.2287+16T>G		intron	N/A	NP_001356804.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	ENST00000377245.9	TSL:1 MANE Select	c.2275+16T>G		intron	N/A	ENSP00000366453.4
	ENSG00000285130	ENST00000642889.1		c.2662+16T>G		intron	N/A	ENSP00000493780.1
	TJP2	ENST00000348208.9	TSL:1	c.2275+16T>G		intron	N/A	ENSP00000345893.4

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5736 AN: 151308 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.00661

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000627

Gnomad FIN AF: 0.000381

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00192

Gnomad OTH AF: 0.0376

GnomAD2 exomes AF: 0.0121 AC: 2914 AN: 240798 AF XY: 0.00951

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000820

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.00534 AC: 7560 AN: 1414980 Hom.: 312 Cov.: 26 AF XY: 0.00475 AC XY: 3351 AN XY: 706152

African (AFR) AF: 0.131 AC: 4253 AN: 32542

American (AMR) AF: 0.0149 AC: 658 AN: 44250

Ashkenazi Jewish (ASJ) AF: 0.00484 AC: 124 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 38968

South Asian (SAS) AF: 0.000588 AC: 50 AN: 85038

European-Finnish (FIN) AF: 0.000819 AC: 43 AN: 52518

Middle Eastern (MID) AF: 0.0203 AC: 112 AN: 5522

European-Non Finnish (NFE) AF: 0.00147 AC: 1574 AN: 1071864

Other (OTH) AF: 0.0127 AC: 746 AN: 58634

GnomAD4 genome AF: 0.0379 AC: 5746 AN: 151420 Hom.: 333 Cov.: 32 AF XY: 0.0365 AC XY: 2704 AN XY: 74026

African (AFR) AF: 0.125 AC: 5140 AN: 41278

American (AMR) AF: 0.0238 AC: 362 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4782

European-Finnish (FIN) AF: 0.000381 AC: 4 AN: 10494

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00192 AC: 130 AN: 67756

Other (OTH) AF: 0.0372 AC: 78 AN: 2096

Alfa AF: 0.0524 Hom.: 200

Bravo AF: 0.0442

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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	-0.66
CADD	Benign	0.26
DANN	Benign	0.80
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs73450890; hg19: chr9-71852905;