Genetic Variant NM_004817.4:c.2858C>G (chr9-69248202-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004817.4(TJP2):c.2858C>G(p.Ser953Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,454,714 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S953L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TJP2
NM_004817.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.15

Publications

0 publications found

Variant links:

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)

TJP2 links:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP2	NM_004817.4 link	c.2858C>G	p.Ser953Trp	missense_variant	Exon 19 of 23	ENST00000377245.9	NP_004808.2	Q9UDY2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9 link	c.2858C>G	p.Ser953Trp	missense_variant	Exon 19 of 23	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 link	c.3245C>G	p.Ser1082Trp	missense_variant	Exon 21 of 25			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.00

AC:

AN:

43298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

85554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108306

Other (OTH)

AF:

0.00

AC:

AN:

60128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

.;.;.;D;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.65

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.8

.;.;.;M;M;M;.;.;.;.;.;.;.

PhyloP100

6.2

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

.;D;.;.;D;D;.;.;.;D;.;D;.

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

.;D;.;.;D;D;.;.;.;D;.;D;.

Sift4G

Pathogenic

0.0

.;D;.;.;D;D;.;.;.;D;.;D;.

Polyphen

1.0

.;.;.;D;D;D;.;.;.;.;.;.;.

Vest4

0.66, 0.56, 0.74, 0.64, 0.74

MutPred

0.24

.;.;.;Loss of phosphorylation at S953 (P = 0.0065);Loss of phosphorylation at S953 (P = 0.0065);Loss of phosphorylation at S953 (P = 0.0065);Loss of phosphorylation at S953 (P = 0.0065);Loss of phosphorylation at S953 (P = 0.0065);.;.;.;.;.;

MVP

0.81

MPC

0.90

ClinPred

1.0

GERP RS

6.2

Varity_R

0.76

gMVP

0.59

Mutation Taster

=48/52

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over