NM_002266.4:c.801A>G

Variant names:

• chr17-68043234-A-G
• rs4638
• NM_002266.4:c.801A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002266.4(KPNA2):​c.801A>G​(p.Val267Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,726 control chromosomes in the GnomAD database, including 409,002 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 0.62 (31131 hom., cov: 32)
  • Exomes 𝑓: 0.71 (377871 hom.)
• Consequence: KPNA2 NM_002266.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 24 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA2	NM_002266.4	MANE Select	c.801A>G	p.Val267Val	synonymous	Exon 7 of 11	NP_002257.1
	KPNA2	NM_001320611.3		c.801A>G	p.Val267Val	synonymous	Exon 7 of 11	NP_001307540.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA2	ENST00000330459.8	TSL:1 MANE Select	c.801A>G	p.Val267Val	synonymous	Exon 7 of 11	ENSP00000332455.3
	KPNA2	ENST00000537025.6	TSL:1	c.801A>G	p.Val267Val	synonymous	Exon 7 of 11	ENSP00000438483.2
	KPNA2	ENST00000579754.2	TSL:2	c.801A>G	p.Val267Val	synonymous	Exon 6 of 10	ENSP00000462331.2

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94719 AN: 151942 Hom.: 31131 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.733

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.656 AC: 165025 AN: 251482 AF XY: 0.664

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.634

Gnomad ASJ exome AF: 0.741

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.706

Gnomad NFE exome AF: 0.739

Gnomad OTH exome AF: 0.688

GnomAD4 exome AF: 0.713 AC: 1041648 AN: 1461666 Hom.: 377871 Cov.: 55 AF XY: 0.712 AC XY: 517964 AN XY: 727152

African (AFR) AF: 0.422 AC: 14133 AN: 33474

American (AMR) AF: 0.639 AC: 28594 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 19324 AN: 26134

East Asian (EAS) AF: 0.281 AC: 11144 AN: 39700

South Asian (SAS) AF: 0.654 AC: 56409 AN: 86256

European-Finnish (FIN) AF: 0.715 AC: 38213 AN: 53420

Middle Eastern (MID) AF: 0.649 AC: 3743 AN: 5768

European-Non Finnish (NFE) AF: 0.746 AC: 829087 AN: 1111802

Other (OTH) AF: 0.679 AC: 41001 AN: 60390

GnomAD4 genome AF: 0.623 AC: 94735 AN: 152060 Hom.: 31131 Cov.: 32 AF XY: 0.619 AC XY: 45984 AN XY: 74316

African (AFR) AF: 0.432 AC: 17919 AN: 41446

American (AMR) AF: 0.644 AC: 9841 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 2544 AN: 3470

East Asian (EAS) AF: 0.282 AC: 1459 AN: 5170

South Asian (SAS) AF: 0.638 AC: 3079 AN: 4824

European-Finnish (FIN) AF: 0.707 AC: 7474 AN: 10576

Middle Eastern (MID) AF: 0.675 AC: 197 AN: 292

European-Non Finnish (NFE) AF: 0.736 AC: 50067 AN: 67990

Other (OTH) AF: 0.647 AC: 1362 AN: 2106

Alfa AF: 0.688 Hom.: 16105

Bravo AF: 0.610

Asia WGS AF: 0.480 AC: 1669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.5
DANN	Benign	0.65
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4638; hg19: chr17-66039350; COSMIC: COSV57857080; COSMIC: COSV57857080;