rs78681604

chr9-69226028-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_004817.4(TJP2):c.1063G>C(p.Gly355Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,614,024 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (11 hom.)
• Consequence: TJP2 NM_004817.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 10.0

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 -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when BayesDel_addAF, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.013994575).
• BP6: Variant 9-69226028-G-C is Benign according to our data. Variant chr9-69226028-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 259550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TJP2	NM_004817.4	c.1063G>C	p.Gly355Arg	missense_variant	7/23	ENST00000377245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP2	ENST00000377245.9	c.1063G>C	p.Gly355Arg	missense_variant	7/23	1	NM_004817.4	P2

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152124 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000879 AC: 221 AN: 251328 Hom.: 2 AF XY: 0.000707 AC XY: 96 AN XY: 135856

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000607

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: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461782 Hom.: 11 Cov.: 31 AF XY: 0.000287 AC XY: 209 AN XY: 727192

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152242 Hom.: 4 Cov.: 33 AF XY: 0.00302 AC XY: 225 AN XY: 74450

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00362

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
Polyphen		1.0	.;.;.;.;D;D;D;.;.;.;.;.;.;.
Vest4		0.90, 0.94, 0.97, 0.96, 0.92
MutPred		0.95		.;.;.;.;Gain of methylation at K352 (P = 0.0394);Gain of methylation at K352 (P = 0.0394);Gain of methylation at K352 (P = 0.0394);Gain of methylation at K352 (P = 0.0394);Gain of methylation at K352 (P = 0.0394);.;.;.;.;.;
MVP		0.79
MPC		0.83
ClinPred		0.10	T
GERP RS		6.0
Varity_R		0.81
gMVP		0.77

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: rs78681604; hg19: chr9-71840944;