chr20-49068716-C-T

Position:

• chr20-49068716-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

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]

CSE1L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.569C>T	p.Ala190Val	missense_variant, splice_region_variant	7/25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.569C>T	p.Ala190Val	missense_variant, splice_region_variant	7/25		NP_001349691.1
CSE1L	NM_001256135.2	c.569C>T	p.Ala190Val	missense_variant, splice_region_variant	7/24		NP_001243064.1
CSE1L	NR_045796.2	n.301-94C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.569C>T	p.Ala190Val	missense_variant, splice_region_variant	7/25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.569C>T	p.Ala190Val	missense_variant, splice_region_variant	7/24	5		ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.569C>T (p.A190V) alteration is located in exon 7 (coding exon 6) of the CSE1L gene. This alteration results from a C to T substitution at nucleotide position 569, causing the alanine (A) at amino acid position 190 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.24
Sift	Benign	0.16	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.55	.;P
Vest4		0.85
MutPred		0.53		Gain of methylation at K189 (P = 0.0539);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-47685253;