19-12702168-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001382241.1(TNPO2):c.2315C>T(p.Thr772Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,612,946 control chromosomes in the GnomAD database, including 40 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 0.0087 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (23 hom.)
• Consequence: TNPO2 NM_001382241.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TNPO2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026058853).
• BP6: Variant 19-12702168-G-A is Benign according to our data. Variant chr19-12702168-G-A is described in ClinVar as [Benign]. Clinvar id is 712233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00868 (1321/152220) while in subpopulation AFR AF= 0.0294 (1222/41540). AF 95% confidence interval is 0.028. There are 17 homozygotes in gnomad4. There are 605 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1319 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO2	NM_001382241.1	c.2315C>T	p.Thr772Met	missense_variant	22/26	ENST00000425528.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO2	ENST00000425528.6	c.2315C>T	p.Thr772Met	missense_variant	22/26	5	NM_001382241.1

Frequencies

GnomAD3 genomes AF: 0.00867 AC: 1319 AN: 152102 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00222 AC: 547 AN: 246350 Hom.: 14 AF XY: 0.00171 AC XY: 230 AN XY: 134310

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000930 AC: 1359 AN: 1460726 Hom.: 23 Cov.: 31 AF XY: 0.000815 AC XY: 592 AN XY: 726690

Gnomad4 AFR exome AF: 0.0308

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000909

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00868 AC: 1321 AN: 152220 Hom.: 17 Cov.: 32 AF XY: 0.00813 AC XY: 605 AN XY: 74428

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00151 Hom.: 4

Bravo AF: 0.00958

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0261 AC: 111

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00272 AC: 329

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.53	T;.
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.12	N;.
REVEL	Benign	0.041
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.028	D;D
Polyphen		0.0020	B;B
Vest4		0.26
MVP		0.082
MPC		1.4
ClinPred		0.022	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs116518190; hg19: chr19-12812982;