NM_004817.4:c.2992-19G>A

Variant names:

• chr9-69251016-G-A
• rs2282335
• NM_004817.4:c.2992-19G>A

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.2992-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,608,104 control chromosomes in the GnomAD database, including 115,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12206 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103320 hom.)
• Consequence: TJP2 NM_004817.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.329
• Publications: 17 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=-0.89).
• BP6: Variant 9-69251016-G-A is Benign according to our data. Variant chr9-69251016-G-A is described in ClinVar as Benign. ClinVar VariationId is 259554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 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.2992-19G>A		intron	N/A	NP_004808.2
	TJP2	NM_001170416.2		c.3085-19G>A		intron	N/A	NP_001163887.1
	TJP2	NM_001369875.1		c.3004-19G>A		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.2992-19G>A		intron	N/A	ENSP00000366453.4
	ENSG00000285130	ENST00000642889.1		c.3379-19G>A		intron	N/A	ENSP00000493780.1
	TJP2	ENST00000348208.9	TSL:1	c.2881-1799G>A		intron	N/A	ENSP00000345893.4

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59819 AN: 151822 Hom.: 12185 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.368

GnomAD2 exomes AF: 0.359 AC: 89319 AN: 248978 AF XY: 0.367

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.161

Gnomad FIN exome AF: 0.469

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.374

GnomAD4 exome AF: 0.372 AC: 542207 AN: 1456164 Hom.: 103320 Cov.: 31 AF XY: 0.375 AC XY: 271942 AN XY: 724930

African (AFR) AF: 0.454 AC: 15153 AN: 33368

American (AMR) AF: 0.211 AC: 9455 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 10636 AN: 26110

East Asian (EAS) AF: 0.216 AC: 8559 AN: 39688

South Asian (SAS) AF: 0.425 AC: 36627 AN: 86122

European-Finnish (FIN) AF: 0.467 AC: 24787 AN: 53112

Middle Eastern (MID) AF: 0.388 AC: 2238 AN: 5762

European-Non Finnish (NFE) AF: 0.373 AC: 412551 AN: 1107078

Other (OTH) AF: 0.369 AC: 22201 AN: 60212

GnomAD4 genome AF: 0.394 AC: 59880 AN: 151940 Hom.: 12206 Cov.: 32 AF XY: 0.396 AC XY: 29404 AN XY: 74272

African (AFR) AF: 0.452 AC: 18724 AN: 41402

American (AMR) AF: 0.295 AC: 4498 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3468

East Asian (EAS) AF: 0.176 AC: 913 AN: 5174

South Asian (SAS) AF: 0.422 AC: 2030 AN: 4806

European-Finnish (FIN) AF: 0.456 AC: 4805 AN: 10542

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26145 AN: 67968

Other (OTH) AF: 0.369 AC: 776 AN: 2104

Alfa AF: 0.382 Hom.: 22063

Bravo AF: 0.377

Asia WGS AF: 0.335 AC: 1167 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

Feb 03, 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

Cholestasis, progressive familial intrahepatic, 4 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypercholanemia, familial 1 Benign:1

Sep 10, 2021

Genome-Nilou Lab

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	-0.89
CADD	Benign	0.11
DANN	Benign	0.64
PhyloP100		-0.33
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: rs2282335; hg19: chr9-71865932; COSMIC: COSV55264244; COSMIC: COSV55264244;