Genetic Variant NM_004817.4:c.2864C>A (chr9-69248208-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004817.4(TJP2):c.2864C>A(p.Pro955Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,444 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P955P) has been classified as Likely benign.

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: 7.71

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 links:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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.2864C>A	p.Pro955Gln	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.2864C>A	p.Pro955Gln	missense_variant	Exon 19 of 23	1	NM_004817.4	ENSP00000366453.4		Q9UDY2-1
ENSG00000285130	ENST00000642889.1 link	c.3251C>A	p.Pro1084Gln	missense_variant	Exon 21 of 25			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450444

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

720726

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

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

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.92

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

0.089

MetaRNN

Uncertain

0.69

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

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.1

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

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.4

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

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.69, 0.64, 0.78, 0.70, 0.73

MutPred

0.26

.;.;.;Loss of glycosylation at T950 (P = 0.1961);Loss of glycosylation at T950 (P = 0.1961);Loss of glycosylation at T950 (P = 0.1961);Loss of glycosylation at T950 (P = 0.1961);Loss of glycosylation at T950 (P = 0.1961);.;.;.;.;.;

MVP

0.73

MPC

0.73

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.56

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over