chr9-69251072-C-T

Variant names:

• chr9-69251072-C-T
• rs41277907
• NM_004817.4:c.3029C>T

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.3029C>T​(p.Ser1010Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,614,074 control chromosomes in the GnomAD database, including 4,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (308 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4223 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.66
• 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: 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=0.0017908514).
• BP6: Variant 9-69251072-C-T is Benign according to our data. Variant chr9-69251072-C-T is described in ClinVar as Benign. ClinVar VariationId is 45110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0765 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.3029C>T	p.Ser1010Phe	missense	Exon 21 of 23	NP_004808.2
	TJP2	NM_001170416.2		c.3122C>T	p.Ser1041Phe	missense	Exon 21 of 23	NP_001163887.1	Q9UDY2-7
	TJP2	NM_001369875.1		c.3041C>T	p.Ser1014Phe	missense	Exon 21 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.3029C>T	p.Ser1010Phe	missense	Exon 21 of 23	ENSP00000366453.4	Q9UDY2-1
	ENSG00000285130	ENST00000642889.1		c.3416C>T	p.Ser1139Phe	missense	Exon 23 of 25	ENSP00000493780.1	A0A2R8YDH4
	TJP2	ENST00000348208.9	TSL:1	c.2881-1743C>T		intron	N/A	ENSP00000345893.4	Q9UDY2-2

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8599 AN: 152150 Hom.: 309 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0505

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0778

Gnomad OTH AF: 0.0617

GnomAD2 exomes AF: 0.0627 AC: 15764 AN: 251338 AF XY: 0.0671

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0924

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0683

Gnomad NFE exome AF: 0.0794

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0730 AC: 106741 AN: 1461806 Hom.: 4223 Cov.: 33 AF XY: 0.0739 AC XY: 53752 AN XY: 727214

African (AFR) AF: 0.0186 AC: 622 AN: 33478

American (AMR) AF: 0.0360 AC: 1610 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0929 AC: 2427 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0833 AC: 7188 AN: 86252

European-Finnish (FIN) AF: 0.0672 AC: 3587 AN: 53410

Middle Eastern (MID) AF: 0.0895 AC: 516 AN: 5768

European-Non Finnish (NFE) AF: 0.0777 AC: 86450 AN: 1111944

Other (OTH) AF: 0.0718 AC: 4334 AN: 60394

GnomAD4 genome AF: 0.0565 AC: 8597 AN: 152268 Hom.: 308 Cov.: 32 AF XY: 0.0573 AC XY: 4268 AN XY: 74472

African (AFR) AF: 0.0207 AC: 858 AN: 41542

American (AMR) AF: 0.0504 AC: 772 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 323 AN: 3468

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.0833 AC: 401 AN: 4816

European-Finnish (FIN) AF: 0.0662 AC: 703 AN: 10616

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0778 AC: 5292 AN: 68014

Other (OTH) AF: 0.0601 AC: 127 AN: 2114

Alfa AF: 0.0685 Hom.: 933

Bravo AF: 0.0528

TwinsUK AF: 0.0798 AC: 296

ALSPAC AF: 0.0773 AC: 298

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.0783 AC: 673

ExAC AF: 0.0636 AC: 7725

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.0872

EpiControl AF: 0.0836

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	0.096
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.087
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.058	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.22
ClinPred		0.027	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.31
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41277907; hg19: chr9-71865988; COSMIC: COSV99601803; COSMIC: COSV99601803;