chr17-47676459-G-A

Position:

• chr17-47676459-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002265.6(KPNB1):​c.1963G>A​(p.Gly655Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KPNB1 NM_002265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

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 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=0.2278043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPNB1	NM_002265.6	c.1963G>A	p.Gly655Ser	missense_variant	16/22	ENST00000290158.9	NP_002256.2
KPNB1	NM_001276453.2	c.1528G>A	p.Gly510Ser	missense_variant	15/21		NP_001263382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNB1	ENST00000290158.9	c.1963G>A	p.Gly655Ser	missense_variant	16/22	1	NM_002265.6	ENSP00000290158	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461270 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726974

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.1963G>A (p.G655S) alteration is located in exon 16 (coding exon 16) of the KPNB1 gene. This alteration results from a G to A substitution at nucleotide position 1963, causing the glycine (G) at amino acid position 655 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.24	.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.66	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.40
MutPred		0.55		.;Loss of ubiquitination at K659 (P = 0.141);.;
MVP		0.42
MPC		1.4
ClinPred		0.51	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-45753825;