rs1013706330

Variant names:

• chr17-68040682-C-G
• rs1013706330
• NM_002266.4:c.218C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-68040682-C-G
• chr17-68040682-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002266.4(KPNA2):​c.218C>G​(p.Thr73Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: KPNA2 NM_002266.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.218C>G	p.Thr73Ser	missense	Exon 4 of 11	NP_002257.1	P52292
	KPNA2	NM_001320611.3		c.218C>G	p.Thr73Ser	missense	Exon 4 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.218C>G	p.Thr73Ser	missense	Exon 4 of 11	ENSP00000332455.3	P52292
	KPNA2	ENST00000537025.6	TSL:1	c.218C>G	p.Thr73Ser	missense	Exon 4 of 11	ENSP00000438483.2	P52292
	KPNA2	ENST00000579754.2	TSL:2	c.218C>G	p.Thr73Ser	missense	Exon 3 of 10	ENSP00000462331.2	P52292

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Benign	0.61
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.062
Sift	Benign	0.94	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.34		Gain of disorder (P = 0.0432)
MVP		0.28
MPC		0.18
ClinPred		0.14	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1013706330; hg19: chr17-66036798; COSMIC: COSV57857300; COSMIC: COSV57857300;