Genetic Variant NM_006390.4:c.2952C>G (chr12-30631959-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006390.4(IPO8):c.2952C>G(p.Ser984Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S984S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IPO8
NM_006390.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.326

Publications

0 publications found

Variant links:

Genes affected

IPO8 (HGNC:9853): (importin 8) The importin-alpha/beta complex and the GTPase Ran mediate nuclear import of proteins with a classical nuclear localization signal. The protein encoded by this gene is a member of a class of approximately 20 potential Ran targets that share a sequence motif related to the Ran-binding site of importin-beta. This protein binds to the nuclear pore complex and, along with RanGTP and RANBP1, inhibits the GAP stimulation of the Ran GTPase. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

IPO8 Gene-Disease associations (from GenCC):

VISS syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

IPO8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4 link	c.2952C>G	p.Ser984Arg	missense_variant	Exon 24 of 25	ENST00000256079.9	NP_006381.2	O15397-1
IPO8	NM_001190995.2 link	c.2337C>G	p.Ser779Arg	missense_variant	Exon 20 of 21		NP_001177924.1	O15397-2
IPO8	XM_017018691.3 link	c.2901C>G	p.Ser967Arg	missense_variant	Exon 24 of 25		XP_016874180.1
IPO8	XM_017018692.2 link	c.2766C>G	p.Ser922Arg	missense_variant	Exon 23 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IPO8	ENST00000256079.9 link	c.2952C>G	p.Ser984Arg	missense_variant	Exon 24 of 25	1	NM_006390.4	ENSP00000256079.4	O15397-1
IPO8	ENST00000544829.5 link	c.2337C>G	p.Ser779Arg	missense_variant	Exon 20 of 21	2		ENSP00000444520.1	O15397-2
IPO8	ENST00000535598.1 link	c.423C>G	p.Ser141Arg	missense_variant	Exon 3 of 3	3		ENSP00000446232.1	H0YH64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250378

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460672

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111896

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

-0.33

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.044

D;T

Polyphen

0.77

P;.

Vest4

0.62

MutPred

0.50

Gain of solvent accessibility (P = 0.1185);.;

MVP

0.54

MPC

0.37

ClinPred

0.75

GERP RS

-7.9

Varity_R

0.23

gMVP

0.56

Mutation Taster

=57/43

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over