12-30636986-T-G

Variant names:

• chr12-30636986-T-G
• rs762550956
• NM_006390.4:c.2691A>C

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.2691A>C​(p.Glu897Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 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)
• Consequence: IPO8 NM_006390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0120

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

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=0.07381591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4	c.2691A>C	p.Glu897Asp	missense_variant	Exon 22 of 25	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.2076A>C	p.Glu692Asp	missense_variant	Exon 18 of 21		NP_001177924.1
IPO8	XM_017018691.3	c.2640A>C	p.Glu880Asp	missense_variant	Exon 22 of 25		XP_016874180.1
IPO8	XM_017018692.2	c.2505A>C	p.Glu835Asp	missense_variant	Exon 21 of 24		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.2691A>C	p.Glu897Asp	missense_variant	Exon 22 of 25	1	NM_006390.4	ENSP00000256079.4
IPO8	ENST00000544829.5	c.2076A>C	p.Glu692Asp	missense_variant	Exon 18 of 21	2		ENSP00000444520.1
IPO8	ENST00000535598.1	c.162A>C	p.Glu54Asp	missense_variant	Exon 1 of 3	3		ENSP00000446232.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000388 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2691A>C (p.E897D) alteration is located in exon 22 (coding exon 22) of the IPO8 gene. This alteration results from a A to C substitution at nucleotide position 2691, causing the glutamic acid (E) at amino acid position 897 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.063	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;.
PhyloP100		-0.012
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.11
Sift	Benign	0.47	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0010	B;.
Vest4		0.081
MutPred		0.23		Gain of catalytic residue at M895 (P = 0.121);.;
MVP		0.53
MPC		0.24
ClinPred		0.061	T
GERP RS		-0.94
PromoterAI		-0.026	Neutral
Varity_R		0.058
gMVP		0.072
Mutation Taster		=89/11	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

Publications

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Other links and lift over

dbSNP: rs762550956; hg19: chr12-30789920;