NM_002264.4:c.1022A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002264.4(KPNA1):​c.1022A>C​(p.Gln341Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q341R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KPNA1
NM_002264.4 missense

Scores

1
2
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.73

Publications

0 publications found
Variant links:
Genes affected
KPNA1 (HGNC:6394): (karyopherin subunit alpha 1) The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC), which consists of 60-100 proteins. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import. This protein interacts with the recombination activating gene 1 (RAG1) protein and is a putative substrate of the RAG1 ubiquitin ligase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]
WDR5B-DT (HGNC:55192): (WDR5B divergent transcript)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15059307).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KPNA1NM_002264.4 linkc.1022A>C p.Gln341Pro missense_variant Exon 11 of 14 ENST00000344337.11 NP_002255.3 P52294

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KPNA1ENST00000344337.11 linkc.1022A>C p.Gln341Pro missense_variant Exon 11 of 14 1 NM_002264.4 ENSP00000343701.6 P52294

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460014
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
726234
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33418
American (AMR)
AF:
0.00
AC:
0
AN:
44458
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26100
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39656
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85748
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53364
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111168
Other (OTH)
AF:
0.00
AC:
0
AN:
60336
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.055
BayesDel_addAF
Benign
-0.022
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
19
DANN
Benign
0.19
DEOGEN2
Benign
0.080
T
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.36
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.0071
T
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-2.6
N
PhyloP100
1.7
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
5.3
N
REVEL
Benign
0.24
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.43
MutPred
0.56
Loss of catalytic residue at Q341 (P = 0.1234);
MVP
0.66
MPC
1.1
ClinPred
0.29
T
GERP RS
5.0
Varity_R
0.44
gMVP
0.78
Mutation Taster
=28/72
disease causing

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

Other links and lift over

dbSNP: rs770263765; hg19: chr3-122156117; COSMIC: COSV100724174; COSMIC: COSV100724174; API