rs2309428

chr9-69228107-C-Achr9-69228107-C-Gchr9-69228107-C-T

Variant summary

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

The NM_004817.4(TJP2):c.1446C>A(p.Asp482Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,606,646 control chromosomes in the GnomAD database, including 519,596 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 0.78 (46428 hom., cov: 31)
  • Exomes 𝑓: 0.81 (473168 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.100

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=8.9933616E-7).
• BP6: Variant 9-69228107-C-A is Benign according to our data. Variant chr9-69228107-C-A is described in ClinVar as [Benign]. Clinvar id is 44091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69228107-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.1446C>A	p.Asp482Glu	missense_variant	9/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.1446C>A	p.Asp482Glu	missense_variant	9/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118094 AN: 151888 Hom.: 46394 Cov.: 31

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.788

GnomAD3 exomes AF: 0.812 AC: 194472 AN: 239456 Hom.: 79354 AF XY: 0.808 AC XY: 104367 AN XY: 129146

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.864

Gnomad ASJ exome AF: 0.822

Gnomad EAS exome AF: 0.889

Gnomad SAS exome AF: 0.743

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.812

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.806 AC: 1171954 AN: 1454640 Hom.: 473168 Cov.: 58 AF XY: 0.804 AC XY: 581022 AN XY: 722790

Gnomad4 AFR exome AF: 0.657

Gnomad4 AMR exome AF: 0.857

Gnomad4 ASJ exome AF: 0.820

Gnomad4 EAS exome AF: 0.910

Gnomad4 SAS exome AF: 0.744

Gnomad4 FIN exome AF: 0.870

Gnomad4 NFE exome AF: 0.806

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.777 AC: 118179 AN: 152006 Hom.: 46428 Cov.: 31 AF XY: 0.780 AC XY: 57949 AN XY: 74274

Gnomad4 AFR AF: 0.662

Gnomad4 AMR AF: 0.820

Gnomad4 ASJ AF: 0.830

Gnomad4 EAS AF: 0.893

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.869

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.788

Alfa AF: 0.805 Hom.: 115053

Bravo AF: 0.769

TwinsUK AF: 0.797 AC: 2957

ALSPAC AF: 0.801 AC: 3087

ESP6500AA AF: 0.658 AC: 2898

ESP6500EA AF: 0.809 AC: 6961

ExAC AF: 0.800 AC: 97085

Asia WGS AF: 0.820 AC: 2851 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	GeneDx	May 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asp459Glu in Exon 10 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 34.3% (1284/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs2309428). -

Cholestasis, progressive familial intrahepatic, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Hypercholanemia, familial 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	3.9
Dann	Benign	0.21
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.51	T;T;T;T;.;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	9.0e-7	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.32	T
Polyphen		0.0	.;.;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.038, 0.023, 0.040, 0.063
MutPred		0.21		.;.;.;.;Gain of glycosylation at P484 (P = 0.0859);Gain of glycosylation at P484 (P = 0.0859);Gain of glycosylation at P484 (P = 0.0859);Gain of glycosylation at P484 (P = 0.0859);Gain of glycosylation at P484 (P = 0.0859);.;.;.;.;.;
MPC		0.18
ClinPred		0.00067	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.12

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: rs2309428; hg19: chr9-71843023; COSMIC: COSV55264387;