rs201977617

chr9-69221188-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004817.4(TJP2):c.644G>A(p.Arg215His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,599,618 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (6 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.36

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005293697).
• BP6: Variant 9-69221188-G-A is Benign according to our data. Variant chr9-69221188-G-A is described in ClinVar as [Benign]. Clinvar id is 178542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.644G>A	p.Arg215His	missense_variant	5/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.644G>A	p.Arg215His	missense_variant	5/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152146 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000811 AC: 176 AN: 217006 Hom.: 1 AF XY: 0.000614 AC XY: 73 AN XY: 118962

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.000429

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000352

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000321 AC: 464 AN: 1447356 Hom.: 6 Cov.: 33 AF XY: 0.000302 AC XY: 217 AN XY: 719098

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000552

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.000804

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152262 Hom.: 3 Cov.: 33 AF XY: 0.00265 AC XY: 197 AN XY: 74448

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00370

ESP6500AA AF: 0.00815 AC: 35

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00105 AC: 124

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg192His in Exon 06 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 0.8% (28/3624) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0053	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.90	N;N;N;N;N;N
PrimateAI	Pathogenic	0.83	D
Polyphen		0.028, 0.017	.;.;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.34, 0.42, 0.33, 0.40, 0.34
MVP		0.70
MPC		0.25
ClinPred		0.0066	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.60

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: rs201977617; hg19: chr9-71836104;