chr12-30647106-G-C

Variant names:

• chr12-30647106-G-C
• rs3910561
• NM_006390.4:c.2268+2031C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006390.4(IPO8):​c.2268+2031C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,016 control chromosomes in the GnomAD database, including 24,656 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24656 hom., cov: 32)
• Consequence: IPO8 NM_006390.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IPO8	NM_006390.4	c.2268+2031C>G		intron_variant	Intron 20 of 24	ENST00000256079.9	NP_006381.2
IPO8	NM_001190995.2	c.1653+2031C>G		intron_variant	Intron 16 of 20		NP_001177924.1
IPO8	XM_017018691.3	c.2217+2031C>G		intron_variant	Intron 20 of 24		XP_016874180.1
IPO8	XM_017018692.2	c.2082+2031C>G		intron_variant	Intron 19 of 23		XP_016874181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IPO8	ENST00000256079.9	c.2268+2031C>G		intron_variant	Intron 20 of 24	1	NM_006390.4	ENSP00000256079.4
IPO8	ENST00000544829.5	c.1653+2031C>G		intron_variant	Intron 16 of 20	2		ENSP00000444520.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84909 AN: 151898 Hom.: 24635 Cov.: 32

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.533

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.559 AC: 84958 AN: 152016 Hom.: 24656 Cov.: 32 AF XY: 0.555 AC XY: 41203 AN XY: 74306

African (AFR) AF: 0.711 AC: 29515 AN: 41498

American (AMR) AF: 0.384 AC: 5868 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1927 AN: 3470

East Asian (EAS) AF: 0.442 AC: 2278 AN: 5152

South Asian (SAS) AF: 0.411 AC: 1981 AN: 4816

European-Finnish (FIN) AF: 0.591 AC: 6232 AN: 10544

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35572 AN: 67950

Other (OTH) AF: 0.532 AC: 1123 AN: 2112

Alfa AF: 0.412 Hom.: 1089

Bravo AF: 0.547

Asia WGS AF: 0.423 AC: 1470 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.80
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs3910561; hg19: chr12-30800040;