19-12702141-G-A

Position:

• chr19-12702141-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001382241.1(TNPO2):​c.2342C>T​(p.Thr781Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO2 NM_001382241.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 19-12702141-G-A is Pathogenic according to our data. Variant chr19-12702141-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3062141.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNPO2	NM_001382241.1	c.2342C>T	p.Thr781Ile	missense_variant	22/26	ENST00000425528.6	NP_001369170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNPO2	ENST00000425528.6	c.2342C>T	p.Thr781Ile	missense_variant	22/26	5	NM_001382241.1	ENSP00000407182.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.;.;T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;.;.;.;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Pathogenic	3.7	H;.;.;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.1	D;D;.;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.99	D;.;.;D;.
Vest4		0.90
MutPred		0.81		Loss of phosphorylation at T781 (P = 0.0335);.;.;Loss of phosphorylation at T781 (P = 0.0335);.;
MVP		0.56
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.98

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.

Other links and lift over

hg19: chr19-12812955;