chr9-69251072-C-T

Position:

• chr9-69251072-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000377245.9(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. 14/20 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 ENST00000377245.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4	c.3029C>T	p.Ser1010Phe	missense_variant	21/23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.3029C>T	p.Ser1010Phe	missense_variant	21/23	1	NM_004817.4	ENSP00000366453	P2

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

GnomAD3 exomes AF: 0.0627 AC: 15764 AN: 251338 Hom.: 598 AF XY: 0.0671 AC XY: 9120 AN XY: 135874

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 SAS exome AF: 0.0802

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

Gnomad4 AFR exome AF: 0.0186

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0929

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0833

Gnomad4 FIN exome AF: 0.0672

Gnomad4 NFE exome AF: 0.0777

Gnomad4 OTH exome AF: 0.0718

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

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.0504

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0833

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0778

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0711 Hom.: 736

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2012	Ser1010Phe in exon 21A of TJP2: This variant is not expected to have clinical si gnificance because it has been identified in 7.8% (673/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS/; dbSNP rs41277907) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.82	T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	.;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	.;.;.;N;.;.;N;N;.
REVEL	Benign	0.087
Sift	Uncertain	0.0040	.;.;.;D;.;.;D;D;.
Sift4G	Uncertain	0.058	.;.;.;T;.;.;D;D;.
Polyphen		0.0	.;.;B;B;.;.;.;.;.
Vest4		0.17, 0.20, 0.080
MPC		0.22
ClinPred		0.027	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs41277907; hg19: chr9-71865988;