chr17-47673020-C-T

Variant names:

• chr17-47673020-C-T
• rs571522744
• NM_002265.6:c.1550C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002265.6(KPNB1):​c.1550C>T​(p.Pro517Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000753 in 1,460,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: KPNB1 NM_002265.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

Genes affected

KPNB1 (HGNC:6400): (karyopherin subunit beta 1) Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. The protein encoded by this gene is a member of the importin beta family. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37650687).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNB1	NM_002265.6	c.1550C>T	p.Pro517Leu	missense_variant, splice_region_variant	Exon 13 of 22	ENST00000290158.9	NP_002256.2
KPNB1	NM_001276453.2	c.1115C>T	p.Pro372Leu	missense_variant, splice_region_variant	Exon 12 of 21		NP_001263382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNB1	ENST00000290158.9	c.1550C>T	p.Pro517Leu	missense_variant, splice_region_variant	Exon 13 of 22	1	NM_002265.6	ENSP00000290158.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250496 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460986 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726814

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: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1550C>T (p.P517L) alteration is located in exon 13 (coding exon 13) of the KPNB1 gene. This alteration results from a C to T substitution at nucleotide position 1550, causing the proline (P) at amino acid position 517 to be replaced by a leucine (L). 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	0.091
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.71	.;D;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.27
Sift	Benign	0.071	T;T;T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.10	.;B;.
Vest4		0.62
MutPred		0.28		.;Loss of disorder (P = 0.0697);.;
MVP		0.79
MPC		1.5
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.59

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: rs571522744; hg19: chr17-45750386;