9-69248059-C-T

Variant names:

• chr9-69248059-C-T
• rs2282336
• NM_004817.4:c.2715C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004817.4(TJP2):​c.2715C>T​(p.Thr905Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,470 control chromosomes in the GnomAD database, including 45,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4421 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41012 hom.)
• Consequence: TJP2 NM_004817.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.820
• Publications: 24 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: PanelApp Australia, 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: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-69248059-C-T is Benign according to our data. Variant chr9-69248059-C-T is described in ClinVar as Benign. ClinVar VariationId is 44105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	NM_004817.4	MANE Select	c.2715C>T	p.Thr905Thr	synonymous	Exon 19 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.2808C>T	p.Thr936Thr	synonymous	Exon 19 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.2727C>T	p.Thr909Thr	synonymous	Exon 19 of 23	NP_001356804.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP2	ENST00000377245.9	TSL:1 MANE Select	c.2715C>T	p.Thr905Thr	synonymous	Exon 19 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.3102C>T	p.Thr1034Thr	synonymous	Exon 21 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.2715C>T	p.Thr905Thr	synonymous	Exon 19 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34915 AN: 152024 Hom.: 4414 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.271 AC: 67968 AN: 250650 AF XY: 0.258

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.436

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.226 AC: 330185 AN: 1461328 Hom.: 41012 Cov.: 36 AF XY: 0.224 AC XY: 162494 AN XY: 726898

African (AFR) AF: 0.174 AC: 5831 AN: 33472

American (AMR) AF: 0.517 AC: 23088 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4276 AN: 26110

East Asian (EAS) AF: 0.435 AC: 17286 AN: 39694

South Asian (SAS) AF: 0.193 AC: 16620 AN: 86212

European-Finnish (FIN) AF: 0.226 AC: 12075 AN: 53374

Middle Eastern (MID) AF: 0.158 AC: 912 AN: 5760

European-Non Finnish (NFE) AF: 0.213 AC: 236748 AN: 1111632

Other (OTH) AF: 0.221 AC: 13349 AN: 60380

GnomAD4 genome AF: 0.230 AC: 34941 AN: 152142 Hom.: 4421 Cov.: 32 AF XY: 0.232 AC XY: 17279 AN XY: 74386

African (AFR) AF: 0.182 AC: 7543 AN: 41506

American (AMR) AF: 0.374 AC: 5719 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 582 AN: 3466

East Asian (EAS) AF: 0.444 AC: 2286 AN: 5152

South Asian (SAS) AF: 0.215 AC: 1036 AN: 4826

European-Finnish (FIN) AF: 0.231 AC: 2443 AN: 10598

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14454 AN: 67990

Other (OTH) AF: 0.239 AC: 504 AN: 2112

Alfa AF: 0.218 Hom.: 1840

Bravo AF: 0.244

Asia WGS AF: 0.311 AC: 1080 AN: 3478

EpiCase AF: 0.207

EpiControl AF: 0.206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cholestasis, progressive familial intrahepatic, 4 (1)
-	-	1	Hypercholanemia, familial 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2282336; hg19: chr9-71862975; COSMIC: COSV55264483;