rs28659989

Variant names:

• chr20-49094187-A-G
• rs28659989
• NM_001316.4:c.2495A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001316.4(CSE1L):​c.2495A>G​(p.Lys832Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 2 publications found

Genes affected

CSE1L (HGNC:2431): (chromosome segregation 1 like) Proteins that carry a nuclear localization signal (NLS) are transported into the nucleus by the importin-alpha/beta heterodimer. Importin-alpha binds the NLS, while importin-beta mediates translocation through the nuclear pore complex. After translocation, RanGTP binds importin-beta and displaces importin-alpha. Importin-alpha must then be returned to the cytoplasm, leaving the NLS protein behind. The protein encoded by this gene binds strongly to NLS-free importin-alpha, and this binding is released in the cytoplasm by the combined action of RANBP1 and RANGAP1. In addition, the encoded protein may play a role both in apoptosis and in cell proliferation. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34135592).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSE1L	NM_001316.4	MANE Select	c.2495A>G	p.Lys832Arg	missense	Exon 23 of 25	NP_001307.2
	CSE1L	NM_001362762.2		c.2495A>G	p.Lys832Arg	missense	Exon 23 of 25	NP_001349691.1
	CSE1L	NM_001256135.2		c.2327A>G	p.Lys776Arg	missense	Exon 22 of 24	NP_001243064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSE1L	ENST00000262982.3	TSL:1 MANE Select	c.2495A>G	p.Lys832Arg	missense	Exon 23 of 25	ENSP00000262982.2
	CSE1L	ENST00000469700.1	TSL:1	n.293A>G		non_coding_transcript_exon	Exon 4 of 6
	CSE1L	ENST00000396192.7	TSL:5	c.2327A>G	p.Lys776Arg	missense	Exon 22 of 24	ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.059	T
Sift4G	Benign	0.067	T
Polyphen		0.85	P
Vest4		0.52
MutPred		0.52		Loss of methylation at K832 (P = 0.0082)
MVP		0.40
MPC		0.67
ClinPred		0.86	D
GERP RS		5.2
Varity_R		0.25
gMVP		0.45
Mutation Taster		=68/32	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: rs28659989; hg19: chr20-47710724;