17-68042150-A-G

Position:

• chr17-68042150-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002266.4(KPNA2):​c.368A>G​(p.Lys123Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: KPNA2 NM_002266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

Genes affected

KPNA2 (HGNC:6395): (karyopherin subunit alpha 2) The import of proteins into the nucleus is a process that involves at least 2 steps. The first is an energy-independent docking of the protein to the nuclear envelope and the second is an energy-dependent translocation through the nuclear pore complex. Imported proteins require a nuclear localization sequence (NLS) which generally consists of a short region of basic amino acids or 2 such regions spaced about 10 amino acids apart. Proteins involved in the first step of nuclear import have been identified in different systems. These include the Xenopus protein importin and its yeast homolog, SRP1 (a suppressor of certain temperature-sensitive mutations of RNA polymerase I in Saccharomyces cerevisiae), which bind to the NLS. KPNA2 protein interacts with the NLSs of DNA helicase Q1 and SV40 T antigen and may be involved in the nuclear transport of proteins. KPNA2 also may play a role in V(D)J recombination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15040347).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KPNA2	NM_002266.4	c.368A>G	p.Lys123Arg	missense_variant	5/11	ENST00000330459.8	NP_002257.1
KPNA2	NM_001320611.3	c.368A>G	p.Lys123Arg	missense_variant	5/11		NP_001307540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNA2	ENST00000330459.8	c.368A>G	p.Lys123Arg	missense_variant	5/11	1	NM_002266.4	ENSP00000332455.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461660 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727142

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Nov 30, 2022

The c.368A>G (p.K123R) alteration is located in exon 5 (coding exon 4) of the KPNA2 gene. This alteration results from a A to G substitution at nucleotide position 368, causing the lysine (K) at amino acid position 123 to be replaced by an arginine (R). 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	0.079
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.060	T;T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.24	N;.;N;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.51	N;.;N;.
REVEL	Benign	0.10
Sift	Benign	0.81	T;.;T;.
Sift4G	Benign	0.81	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.25
MutPred		0.62		Loss of ubiquitination at K123 (P = 0.0309);Loss of ubiquitination at K123 (P = 0.0309);Loss of ubiquitination at K123 (P = 0.0309);Loss of ubiquitination at K123 (P = 0.0309);
MVP		0.45
MPC		0.16
ClinPred		0.57	D
GERP RS		4.6
Varity_R		0.26
gMVP		0.35

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: rs781793354; hg19: chr17-66038266;