9-69237088-T-C

Position:

• chr9-69237088-T-C

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.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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (137 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (112 hom.)
• Consequence: TJP2 ENST00000377245.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.94

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=0.001763612).
• BP6: Variant 9-69237088-T-C is Benign according to our data. Variant chr9-69237088-T-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4	c.2131T>C	p.Ser711Pro	missense_variant	14/23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.2131T>C	p.Ser711Pro	missense_variant	14/23	1	NM_004817.4	ENSP00000366453	P2

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

GnomAD3 exomes AF: 0.00598 AC: 1504 AN: 251490 Hom.: 52 AF XY: 0.00435 AC XY: 591 AN XY: 135920

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.0781

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.00541

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

Gnomad4 AFR AF: 0.0814

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00504 Hom.: 44

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

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	May 07, 2012	Ser688Pro in Exon 15 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 8.5% (318/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35797487). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.63	.;.;.;.;N;N;N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.7	.;N;.;.;.;N;N;.;.;.;N;.;N;.
REVEL	Benign	0.061
Sift	Benign	0.55	.;T;.;.;.;T;T;.;.;.;T;.;T;.
Sift4G	Benign	1.0	.;T;.;.;.;T;T;.;.;.;T;.;T;.
Polyphen		0.0, 0.0010	.;.;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.17, 0.21, 0.21, 0.23
MVP		0.51
MPC		0.25
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.057
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs35797487; hg19: chr9-71852004;