12-30637024-C-T

Position:

• chr12-30637024-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.2653G>A​(p.Glu885Lys) 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 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IPO8 NM_006390.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

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=0.15709049).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IPO8	NM_006390.4	c.2653G>A	p.Glu885Lys	missense_variant	22/25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2038G>A	p.Glu680Lys	missense_variant	18/21		NP_001177924.1
IPO8	XM_017018691.3	c.2602G>A	p.Glu868Lys	missense_variant	22/25		XP_016874180.1
IPO8	XM_017018692.2	c.2467G>A	p.Glu823Lys	missense_variant	21/24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.2653G>A	p.Glu885Lys	missense_variant	22/25	1	NM_006390.4	ENSP00000256079	P1
IPO8	ENST00000544829.5	c.2038G>A	p.Glu680Lys	missense_variant	18/21	2		ENSP00000444520
IPO8	ENST00000535598.1	c.127G>A	p.Glu43Lys	missense_variant	1/3	3		ENSP00000446232

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.18
Sift	Benign	0.065	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.0060	B;.
Vest4		0.30
MutPred		0.46		Gain of MoRF binding (P = 0.0065);.;
MVP		0.52
MPC		0.30
ClinPred		0.69	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs751369714; hg19: chr12-30789958; COSMIC: COSV56239598;