Genetic Variant NM_002266.4:c.212A>G (chr17-68037494-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002266.4(KPNA2):c.212A>G(p.Gln71Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KPNA2
NM_002266.4 missense, splice_region

Scores

Splicing: ADA: 0.9923

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.23

Variant links:

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]

KPNA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KPNA2	NM_002266.4 link	c.212A>G	p.Gln71Arg	missense_variant, splice_region_variant	Exon 3 of 11	ENST00000330459.8	NP_002257.1	P52292
KPNA2	NM_001320611.3 link	c.212A>G	p.Gln71Arg	missense_variant, splice_region_variant	Exon 3 of 11		NP_001307540.1	P52292

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KPNA2	ENST00000330459.8 link	c.212A>G	p.Gln71Arg	missense_variant, splice_region_variant	Exon 3 of 11	1	NM_002266.4	ENSP00000332455.3		P52292

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725430

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.081

T;T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.0083

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

.;T;D;D

M_CAP

Benign

0.0099

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.;M;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

N;.;N;.

REVEL

Benign

0.087

Sift

Benign

0.21

T;.;T;.

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.20

MutPred

0.35

Gain of MoRF binding (P = 0.0331);Gain of MoRF binding (P = 0.0331);Gain of MoRF binding (P = 0.0331);Gain of MoRF binding (P = 0.0331);

MVP

0.61

MPC

0.22

ClinPred

0.89

GERP RS

4.3

Varity_R

0.38

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.73

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over