rs1290509499

Variant names:

• chr20-49070232-A-G
• rs1290509499
• NM_001316.4:c.703A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001316.4(CSE1L):​c.703A>G​(p.Met235Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,314,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.01
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSE1L	NM_001316.4	MANE Select	c.703A>G	p.Met235Val	missense	Exon 8 of 25	NP_001307.2
	CSE1L	NM_001362762.2		c.703A>G	p.Met235Val	missense	Exon 8 of 25	NP_001349691.1	P55060-3
	CSE1L	NM_001256135.2		c.703A>G	p.Met235Val	missense	Exon 8 of 24	NP_001243064.1	P55060-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSE1L	ENST00000262982.3	TSL:1 MANE Select	c.703A>G	p.Met235Val	missense	Exon 8 of 25	ENSP00000262982.2	P55060-1
	CSE1L	ENST00000889064.1		c.703A>G	p.Met235Val	missense	Exon 9 of 26	ENSP00000559123.1
	CSE1L	ENST00000933032.1		c.703A>G	p.Met235Val	missense	Exon 8 of 25	ENSP00000603091.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 226178 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: 0.00000304 AC: 4 AN: 1314514 Hom.: 0 Cov.: 22 AF XY: 0.00000456 AC XY: 3 AN XY: 658586

African (AFR) AF: 0.00 AC: 0 AN: 29484

American (AMR) AF: 0.00 AC: 0 AN: 36760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24574

East Asian (EAS) AF: 0.00 AC: 0 AN: 38032

South Asian (SAS) AF: 0.00 AC: 0 AN: 75336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.00000401 AC: 4 AN: 996844

Other (OTH) AF: 0.00 AC: 0 AN: 55174

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.58
Sift	Benign	0.28	T
Sift4G	Uncertain	0.010	D
Polyphen		0.97	D
Vest4		0.84
MutPred		0.68		Gain of catalytic residue at M235 (P = 0.0047)
MVP		0.72
MPC		0.48
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.75
Mutation Taster		=60/40	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: rs1290509499; hg19: chr20-47686769;