chr17-68045919-G-A

Variant names:

• chr17-68045919-G-A
• rs1391419820
• NM_002266.4:c.1495G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002266.4(KPNA2):​c.1495G>A​(p.Glu499Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000511 in 1,566,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: KPNA2 NM_002266.4 missense, splice_region
• Scores: Splicing: ADA: 0.9110
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002266.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA2	NM_002266.4	MANE Select	c.1495G>A	p.Glu499Lys	missense splice_region	Exon 10 of 11	NP_002257.1	P52292
	KPNA2	NM_001320611.3		c.1495G>A	p.Glu499Lys	missense splice_region	Exon 10 of 11	NP_001307540.1	P52292

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA2	ENST00000330459.8	TSL:1 MANE Select	c.1495G>A	p.Glu499Lys	missense splice_region	Exon 10 of 11	ENSP00000332455.3	P52292
	KPNA2	ENST00000537025.6	TSL:1	c.1495G>A	p.Glu499Lys	missense splice_region	Exon 10 of 11	ENSP00000438483.2	P52292
	KPNA2	ENST00000676594.1		c.1495G>A	p.Glu499Lys	missense	Exon 10 of 11	ENSP00000503445.1	A0A7I2YQE1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1413992 Hom.: 0 Cov.: 27 AF XY: 0.00000427 AC XY: 3 AN XY: 702728

African (AFR) AF: 0.00 AC: 0 AN: 31684

American (AMR) AF: 0.00 AC: 0 AN: 37590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24544

East Asian (EAS) AF: 0.00 AC: 0 AN: 39272

South Asian (SAS) AF: 0.00 AC: 0 AN: 79286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.00000553 AC: 6 AN: 1085684

Other (OTH) AF: 0.00 AC: 0 AN: 58374

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.028	D
Sift4G	Benign	0.16	T
Polyphen		0.076	B
Vest4		0.87
MutPred		0.50		Gain of ubiquitination at E499 (P = 0.0094)
MVP		0.79
MPC		0.67
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.48
gMVP		0.46
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.72
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: rs1391419820; hg19: chr17-66042035; COSMIC: COSV100388789; COSMIC: COSV100388789;