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Intellectual disability

Gene: TNPO2

Amber List (moderate evidence)

TNPO2 (transportin 2)
EnsemblGeneIds (GRCh38): ENSG00000105576
EnsemblGeneIds (GRCh37): ENSG00000105576
OMIM: 603002, Gene2Phenotype
TNPO2 is in 3 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Upgraded from Red to Amber but there are now sufficient unrelated cases with a relevant phenotype associated with various variants in this gene to rate as Green at the next GMS panel update.
Created: 23 Sep 2021, 10 a.m. | Last Modified: 23 Sep 2021, 10 a.m.
Panel Version: 3.1305
Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

Notably 6 individuals had additional SNVs/CNVs of uncertain significance, some of which include known ID genes (e.g. SETBP1, CUX2, ARMC9, PDE4D), but were discounted due to lack of explanation of the overall patient phenotype.

Some functional studies conducted in Drosophila demonstrated that patient-associated variants caused neurodevelopmental defects that were dosage and location (of variant within protein) dependent.
Created: 23 Sep 2021, 9:55 a.m. | Last Modified: 23 Sep 2021, 9:55 a.m.
Panel Version: 3.1301

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

PMID: 34314705 - 15 individuals reported with de novo missense variants and a variety of clinical features including intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia).

Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in "toxicity" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF.

gnomAD: minimal PTCs present
Created: 7 Aug 2021, 6:30 a.m. | Last Modified: 7 Aug 2021, 6:30 a.m.
Panel Version: 3.1216

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; dysmorphic features

Publications

Variants in this GENE are reported as part of current diagnostic practice

Caroline Wright (Sanger)

Red List (low evidence)

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

Insufficient ID evidence for inclusion on panel.
Created: 31 Oct 2017, 9:24 a.m.

Publications

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Intellectual disability
  • Dysmorphic features
  • Microcephaly
  • Seizures
  • Hypotonia
Tags
Q3_21_rating
OMIM
603002
Clinvar variants
Variants in TNPO2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

23 Sep 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: tnpo2 has been classified as Amber List (Moderate Evidence).

23 Sep 2021, Gel status: 1

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: TNPO2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

23 Sep 2021, Gel status: 1

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TNPO2 were changed from to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia

23 Sep 2021, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: TNPO2 were set to 26350204

23 Sep 2021, Gel status: 1

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_21_rating tag was added to gene: TNPO2.

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene TNPO2 was set to ['26350204']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

TNPO2 was created by ellenmcdonagh

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

TNPO2 was added to Intellectual disabilitypanel. Sources: Expert Review Red