rs35797487

Variant names:

• chr9-69237088-T-C
• rs35797487
• NM_004817.4:c.2131T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-69237088-T-C
• chr9-69237088-T-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.2131T>C​(p.Ser711Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,614,128 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (137 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (112 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.94
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001763612).
• BP6: Variant 9-69237088-T-C is Benign according to our data. Variant chr9-69237088-T-C is described in ClinVar as Benign. ClinVar VariationId is 178641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0791 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.2131T>C	p.Ser711Pro	missense	Exon 14 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.2224T>C	p.Ser742Pro	missense	Exon 14 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.2143T>C	p.Ser715Pro	missense	Exon 14 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.2131T>C	p.Ser711Pro	missense	Exon 14 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.2518T>C	p.Ser840Pro	missense	Exon 16 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.2131T>C	p.Ser711Pro	missense	Exon 14 of 21	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3543 AN: 152122 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.0814

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00598 AC: 1504 AN: 251490 AF XY: 0.00435

Gnomad AFR exome AF: 0.0802

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00235 AC: 3436 AN: 1461888 Hom.: 112 Cov.: 32 AF XY: 0.00208 AC XY: 1510 AN XY: 727248

African (AFR) AF: 0.0781 AC: 2616 AN: 33478

American (AMR) AF: 0.00429 AC: 192 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000233 AC: 259 AN: 1112010

Other (OTH) AF: 0.00541 AC: 327 AN: 60394

GnomAD4 genome AF: 0.0233 AC: 3554 AN: 152240 Hom.: 137 Cov.: 32 AF XY: 0.0224 AC XY: 1670 AN XY: 74450

African (AFR) AF: 0.0814 AC: 3380 AN: 41532

American (AMR) AF: 0.00706 AC: 108 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68012

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.00887 Hom.: 100

Bravo AF: 0.0262

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0853 AC: 376

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00741 AC: 899

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.63	N
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.061
Sift	Benign	0.55	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.51
MPC		0.25
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.057
gMVP		0.47
Mutation Taster		=97/3	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: rs35797487; hg19: chr9-71852004;