chr17-68044059-T-C

Variant names:

• chr17-68044059-T-C
• rs1136739
• NM_002266.4:c.1152T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002266.4(KPNA2):​c.1152T>C​(p.Ser384Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 1,611,560 control chromosomes in the GnomAD database, including 731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (370 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (361 hom.)
• Consequence: KPNA2 NM_002266.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.474
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-68044059-T-C is Benign according to our data. Variant chr17-68044059-T-C is described in ClinVar as Benign. ClinVar VariationId is 769922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA2	NM_002266.4	MANE Select	c.1152T>C	p.Ser384Ser	synonymous	Exon 8 of 11	NP_002257.1	P52292
	KPNA2	NM_001320611.3		c.1152T>C	p.Ser384Ser	synonymous	Exon 8 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.1152T>C	p.Ser384Ser	synonymous	Exon 8 of 11	ENSP00000332455.3	P52292
	KPNA2	ENST00000537025.6	TSL:1	c.1152T>C	p.Ser384Ser	synonymous	Exon 8 of 11	ENSP00000438483.2	P52292
	KPNA2	ENST00000579754.2	TSL:2	c.1152T>C	p.Ser384Ser	synonymous	Exon 7 of 10	ENSP00000462331.2	P52292

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5889 AN: 152192 Hom.: 367 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00983 AC: 2467 AN: 250924 AF XY: 0.00735

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00876

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00409 AC: 5967 AN: 1459250 Hom.: 361 Cov.: 30 AF XY: 0.00354 AC XY: 2568 AN XY: 726216

African (AFR) AF: 0.136 AC: 4512 AN: 33264

American (AMR) AF: 0.0100 AC: 449 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00886 AC: 51 AN: 5758

European-Non Finnish (NFE) AF: 0.000319 AC: 354 AN: 1109798

Other (OTH) AF: 0.00925 AC: 558 AN: 60296

GnomAD4 genome AF: 0.0388 AC: 5916 AN: 152310 Hom.: 370 Cov.: 32 AF XY: 0.0383 AC XY: 2854 AN XY: 74492

African (AFR) AF: 0.133 AC: 5533 AN: 41534

American (AMR) AF: 0.0187 AC: 286 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68038

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0196 Hom.: 86

Bravo AF: 0.0446

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.2
DANN	Benign	0.62
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1136739; hg19: chr17-66040175;