NM_001366306.2:c.40A>C

Variant names:

• chr6-116689355-A-C
• rs756179244
• NM_001366306.2:c.40A>C

Variant summary

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

The NM_001366306.2(KPNA5):​c.40A>C​(p.Met14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. M14I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KPNA5 NM_001366306.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73
• Publications: 0 publications found

Genes affected

KPNA5 (HGNC:6398): (karyopherin subunit alpha 5) 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 and is probably 120 million daltons in molecular size. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion; larger molecules are transported by an active process. Most nuclear proteins contain short basic amino acid sequences known as nuclear localization signals (NLSs). KPNA5 protein belongs to the importin alpha protein family and is thought to be involved in NLS-dependent protein import into the nucleus. [provided by RefSeq, Jul 2008]

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=0.16025376).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366306.2. 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
	KPNA5	NM_001366306.2	MANE Select	c.40A>C	p.Met14Leu	missense	Exon 2 of 14	NP_001353235.1	O15131
	KPNA5	NM_001366304.1		c.100A>C	p.Met34Leu	missense	Exon 3 of 16	NP_001353233.1	A0A8V8TMV2
	KPNA5	NM_001366305.2		c.100A>C	p.Met34Leu	missense	Exon 3 of 15	NP_001353234.1	A0A8V8TMV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA5	ENST00000368564.7	TSL:1 MANE Select	c.40A>C	p.Met14Leu	missense	Exon 2 of 14	ENSP00000357552.1	O15131
	KPNA5	ENST00000356348.6	TSL:1	c.40A>C	p.Met14Leu	missense	Exon 2 of 15	ENSP00000348704.1	O15131
	KPNA5	ENST00000937498.1		c.40A>C	p.Met14Leu	missense	Exon 2 of 15	ENSP00000607557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456450 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724566

African (AFR) AF: 0.00 AC: 0 AN: 33058

American (AMR) AF: 0.00 AC: 0 AN: 43234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110314

Other (OTH) AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.082
Sift	Benign	0.71	T
Sift4G	Benign	1.0	T
Vest4		0.43
MutPred		0.45		Loss of methylation at K6 (P = 0.0559)
MVP		0.24
MPC		0.82
ClinPred		0.70	D
GERP RS		5.4
gMVP		0.38
Mutation Taster		=84/16	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: rs756179244; hg19: chr6-117010518;