20-49068716-C-T

Variant names:

• chr20-49068716-C-T
• NM_001316.4:c.569C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001316.4(CSE1L):​c.569C>T​(p.Ala190Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSE1L NM_001316.4 missense, splice_region
• Scores: Splicing: ADA: 0.9821
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.569C>T	p.Ala190Val	missense splice_region	Exon 7 of 25	NP_001307.2
	CSE1L	NM_001362762.2		c.569C>T	p.Ala190Val	missense splice_region	Exon 7 of 25	NP_001349691.1	P55060-3
	CSE1L	NM_001256135.2		c.569C>T	p.Ala190Val	missense splice_region	Exon 7 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.569C>T	p.Ala190Val	missense splice_region	Exon 7 of 25	ENSP00000262982.2	P55060-1
	CSE1L	ENST00000889064.1		c.569C>T	p.Ala190Val	missense splice_region	Exon 8 of 26	ENSP00000559123.1
	CSE1L	ENST00000933032.1		c.569C>T	p.Ala190Val	missense splice_region	Exon 7 of 25	ENSP00000603091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

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	0.21
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.55	P
Vest4		0.85
MutPred		0.53		Gain of methylation at K189 (P = 0.0539)
MVP		0.34
MPC		0.68
ClinPred		0.72	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.54
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.86
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

hg19: chr20-47685253;