rs28556975

Positions:

• chr9-69248154-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004817.4(TJP2):​c.2810T>C​(p.Leu937Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,613,820 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (23 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.05

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=0.0074647665).
• BP6: Variant 9-69248154-T-C is Benign according to our data. Variant chr9-69248154-T-C is described in ClinVar as [Benign]. Clinvar id is 178680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00783 (1192/152228) while in subpopulation AFR AF= 0.0272 (1129/41522). AF 95% confidence interval is 0.0259. There are 22 homozygotes in gnomad4. There are 576 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP2	NM_004817.4	c.2810T>C	p.Leu937Pro	missense_variant	19/23	ENST00000377245.9	NP_004808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP2	ENST00000377245.9	c.2810T>C	p.Leu937Pro	missense_variant	19/23	1	NM_004817.4	ENSP00000366453	P2

Frequencies

GnomAD3 genomes AF: 0.00780 AC: 1186 AN: 152110 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00219 AC: 546 AN: 249634 Hom.: 9 AF XY: 0.00154 AC XY: 208 AN XY: 135140

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000844 AC: 1233 AN: 1461592 Hom.: 23 Cov.: 32 AF XY: 0.000697 AC XY: 507 AN XY: 727098

Gnomad4 AFR exome AF: 0.0311

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00783 AC: 1192 AN: 152228 Hom.: 22 Cov.: 32 AF XY: 0.00774 AC XY: 576 AN XY: 74442

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00197 Hom.: 9

Bravo AF: 0.00912

ESP6500AA AF: 0.0284 AC: 125

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2013	Leu937Pro in Exon 19E of TJP2: This variant is not expected to have clinical sig nificance because it has been identified in 2.8% (125/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs28556975). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;.;.;D;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0075	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	.;.;.;L;L;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	.;D;.;.;D;D;.;.;.;D;.;D;.
REVEL	Benign	0.10
Sift	Benign	0.064	.;T;.;.;T;D;.;.;.;T;.;D;.
Sift4G	Benign	0.12	.;T;.;.;T;T;.;.;.;T;.;T;.
Polyphen		0.75, 0.59	.;.;.;P;P;P;.;.;.;.;.;.;.
Vest4		0.51, 0.54, 0.54, 0.51, 0.39
MVP		0.75
MPC		0.67
ClinPred		0.014	T
GERP RS		6.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.8
Varity_R		0.61
gMVP		0.41

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: rs28556975; hg19: chr9-71863070;