rs377285436

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-30632009-C-A
• chr12-30632009-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 15/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4	c.2902G>T	p.Val968Leu	missense_variant, splice_region_variant	Exon 24 of 25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2287G>T	p.Val763Leu	missense_variant, splice_region_variant	Exon 20 of 21		NP_001177924.1
IPO8	XM_017018691.3	c.2851G>T	p.Val951Leu	missense_variant, splice_region_variant	Exon 24 of 25		XP_016874180.1
IPO8	XM_017018692.2	c.2716G>T	p.Val906Leu	missense_variant, splice_region_variant	Exon 23 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.2902G>T	p.Val968Leu	missense_variant, splice_region_variant	Exon 24 of 25	1	NM_006390.4	ENSP00000256079.4
IPO8	ENST00000544829.5	c.2287G>T	p.Val763Leu	missense_variant, splice_region_variant	Exon 20 of 21	2		ENSP00000444520.1
IPO8	ENST00000535598.1	c.373G>T	p.Val125Leu	missense_variant, splice_region_variant	Exon 3 of 3	3		ENSP00000446232.1

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

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: 0.00000451

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.35	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;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

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: chr12-30784943;