chr17-68040682-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002266.4(KPNA2):​c.218C>T​(p.Thr73Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KPNA2 NM_002266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17711776).

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>T	p.Thr73Ile	missense	Exon 4 of 11	NP_002257.1	P52292
	KPNA2	NM_001320611.3		c.218C>T	p.Thr73Ile	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>T	p.Thr73Ile	missense	Exon 4 of 11	ENSP00000332455.3	P52292
	KPNA2	ENST00000537025.6	TSL:1	c.218C>T	p.Thr73Ile	missense	Exon 4 of 11	ENSP00000438483.2	P52292
	KPNA2	ENST00000579754.2	TSL:2	c.218C>T	p.Thr73Ile	missense	Exon 3 of 10	ENSP00000462331.2	P52292

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454340 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723818

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1105890

Other (OTH) AF: 0.00 AC: 0 AN: 60044

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000417739), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.043
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.020	B
Vest4		0.32
MutPred		0.32		Loss of disorder (P = 0.0473)
MVP		0.34
MPC		0.37
ClinPred		0.63	D
GERP RS		4.5
Varity_R		0.31
gMVP		0.13
Mutation Taster		=74/26	polymorphism

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: rs1013706330; hg19: chr17-66036798;