chr12-30632009-C-A

Variant names:

• chr12-30632009-C-A
• rs377285436
• NM_006390.4:c.2902G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006390.4(IPO8):​c.2902G>T​(p.Val968Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V968M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: IPO8 NM_006390.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.514
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12381965).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006390.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPO8	NM_006390.4	MANE Select	c.2902G>T	p.Val968Leu	missense splice_region	Exon 24 of 25	NP_006381.2
	IPO8	NM_001190995.2		c.2287G>T	p.Val763Leu	missense splice_region	Exon 20 of 21	NP_001177924.1	O15397-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPO8	ENST00000256079.9	TSL:1 MANE Select	c.2902G>T	p.Val968Leu	missense splice_region	Exon 24 of 25	ENSP00000256079.4	O15397-1
	IPO8	ENST00000910950.1		c.2998G>T	p.Val1000Leu	missense splice_region	Exon 25 of 26	ENSP00000581009.1
	IPO8	ENST00000910953.1		c.2995G>T	p.Val999Leu	missense splice_region	Exon 25 of 26	ENSP00000581012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456936 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724906

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109852

Other (OTH) AF: 0.0000166 AC: 1 AN: 60256

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.21
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.51
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.25
MutPred		0.46		Loss of helix (P = 0.0376)
MVP		0.26
MPC		0.26
ClinPred		0.48	T
GERP RS		5.0
Varity_R		0.081
gMVP		0.27
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs377285436; hg19: chr12-30784943;