chr20-49085350-C-A

Position:

• chr20-49085350-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001316.4(CSE1L):​c.1687C>A​(p.Leu563Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CSE1L
• BP4: Computational evidence support a benign effect (MetaRNN=0.13145602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSE1L	NM_001316.4	c.1687C>A	p.Leu563Ile	missense_variant	16/25	ENST00000262982.3
CSE1L	NM_001362762.2	c.1687C>A	p.Leu563Ile	missense_variant	16/25
CSE1L	NM_001256135.2	c.1519C>A	p.Leu507Ile	missense_variant	15/24
CSE1L	NR_045796.2	n.1325C>A		non_coding_transcript_exon_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSE1L	ENST00000262982.3	c.1687C>A	p.Leu563Ile	missense_variant	16/25	1	NM_001316.4	P1
CSE1L	ENST00000396192.7	c.1519C>A	p.Leu507Ile	missense_variant	15/24	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

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

May 06, 2022

The c.1687C>A (p.L563I) alteration is located in exon 16 (coding exon 15) of the CSE1L gene. This alteration results from a C to A substitution at nucleotide position 1687, causing the leucine (L) at amino acid position 563 to be replaced by an isoleucine (I). 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	0.067
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.17
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.16
Sift	Benign	0.44	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0010	.;B
Vest4		0.33
MutPred		0.59		.;Gain of ubiquitination at K559 (P = 0.1375);
MVP		0.22
MPC		0.47
ClinPred		0.49	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.17

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-47701887;