rs1167037164

Variant names:

• chr17-68037494-A-G
• rs1167037164
• NM_002266.4:c.212A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-68037494-A-G
• chr17-68037494-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q71L) has been classified as Uncertain significance.

• 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
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.212A>G	p.Gln71Arg	missense splice_region	Exon 3 of 11	NP_002257.1	P52292
	KPNA2	NM_001320611.3		c.212A>G	p.Gln71Arg	missense splice_region	Exon 3 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.212A>G	p.Gln71Arg	missense splice_region	Exon 3 of 11	ENSP00000332455.3	P52292
	KPNA2	ENST00000537025.6	TSL:1	c.212A>G	p.Gln71Arg	missense splice_region	Exon 3 of 11	ENSP00000438483.2	P52292
	KPNA2	ENST00000579754.2	TSL:2	c.212A>G	p.Gln71Arg	missense splice_region	Exon 2 of 10	ENSP00000462331.2	P52292

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458512 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725430

African (AFR) AF: 0.0000300 AC: 1 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 43792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110772

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0083
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.087
Sift	Benign	0.21	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.35		Gain of MoRF binding (P = 0.0331)
MVP		0.61
MPC		0.22
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.38
gMVP		0.35
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs1167037164; hg19: chr17-66033610;