Variant 19-12703720-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001382241.1(TNPO2):c.2104T>A(p.Cys702Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TNPO2
NM_001382241.1 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 8.70

Variant links:

Genes affected

TNPO2 (HGNC:19998): (transportin 2) Predicted to enable nuclear import signal receptor activity and nuclear localization sequence binding activity. Predicted to be involved in protein import into nucleus. Predicted to act upstream of or within negative regulation of muscle cell differentiation. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TNPO2 links:

SNORD135 (HGNC:50416): (small nucleolar RNA, C/D box 135)

SNORD135 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the TNPO2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 5.8776 (above the threshold of 3.09). Trascript score misZ: 6.7753 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNPO2	NM_001382241.1 link	c.2104T>A	p.Cys702Ser	missense_variant	19/26	ENST00000425528.6	NP_001369170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNPO2	ENST00000425528.6 link	c.2104T>A	p.Cys702Ser	missense_variant	19/26	5	NM_001382241.1	ENSP00000407182.1		O14787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455742

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TNPO2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The TNPO2 c.2104T>A variant is predicted to result in the amino acid substitution p.Cys702Ser. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.29

T;.;.;T;.

Eigen

Benign

0.084

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.;.;.;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.5

L;L;L;L;L

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.2

D;D;D;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.39

T;T;T;.;.

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.024

B;.;.;B;.

Vest4

0.81

MutPred

0.56

Loss of catalytic residue at P701 (P = 0.0235);Loss of catalytic residue at P701 (P = 0.0235);Loss of catalytic residue at P701 (P = 0.0235);Loss of catalytic residue at P701 (P = 0.0235);Loss of catalytic residue at P701 (P = 0.0235);

MVP

0.46

MPC

1.6

ClinPred

0.84

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over