rs41277901

chr9-69229208-G-Achr9-69229208-G-T

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.1478G>A(p.Arg493Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00335 in 1,614,078 control chromosomes in the GnomAD database, including 70 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (44 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.23

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=0.0020357668).
• BP6: Variant 9-69229208-G-A is Benign according to our data. Variant chr9-69229208-G-A is described in ClinVar as [Benign]. Clinvar id is 44092.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 = 0.0122 (1856/152256) while in subpopulation AFR AF= 0.036 (1497/41536). AF 95% confidence interval is 0.0345. There are 26 homozygotes in gnomad4. There are 910 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.1478G>A	p.Arg493Lys	missense_variant	10/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.1478G>A	p.Arg493Lys	missense_variant	10/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1854 AN: 152138 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00468 AC: 1177 AN: 251486 Hom.: 12 AF XY: 0.00394 AC XY: 535 AN XY: 135918

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00243 AC: 3547 AN: 1461822 Hom.: 44 Cov.: 31 AF XY: 0.00226 AC XY: 1645 AN XY: 727226

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.00778

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00599

GnomAD4 genome AF: 0.0122 AC: 1856 AN: 152256 Hom.: 26 Cov.: 32 AF XY: 0.0122 AC XY: 910 AN XY: 74448

Gnomad4 AFR AF: 0.0360

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00146

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.00388 Hom.: 12

Bravo AF: 0.0149

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0347 AC: 153

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00511 AC: 620

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg470Lys in Exon 11 of TJP2: This variant is not expected to have clinical sign ificance because it has been identified in 3.6% (134/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs41277901). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2018	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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	20
Dann	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;D;D;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.61	D;D;D;D;D;D
PrimateAI	Benign	0.44	T
Polyphen		0.0070, 0.0040	.;.;.;.;B;B;B;.;.;.;.;.;.;.
Vest4		0.23, 0.25, 0.26, 0.24
MVP		0.40
MPC		0.20
ClinPred		0.010	T
GERP RS		4.0
Varity_R		0.075
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41277901; hg19: chr9-71844124;