20-49070246-G-A

Position:

• chr20-49070246-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001316.4(CSE1L):​c.717G>A​(p.Met239Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,319,574 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: 0.0000015 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.66

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.717G>A	p.Met239Ile	missense_variant	8/25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.717G>A	p.Met239Ile	missense_variant	8/25		NP_001349691.1
CSE1L	NM_001256135.2	c.717G>A	p.Met239Ile	missense_variant	8/24		NP_001243064.1
CSE1L	NR_045796.2	n.355G>A		non_coding_transcript_exon_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.717G>A	p.Met239Ile	missense_variant	8/25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.717G>A	p.Met239Ile	missense_variant	8/24	5		ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1319574 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 660630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

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

Feb 16, 2023

The c.717G>A (p.M239I) alteration is located in exon 8 (coding exon 7) of the CSE1L gene. This alteration results from a G to A substitution at nucleotide position 717, causing the methionine (M) at amino acid position 239 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.052	T;T
Polyphen		0.99	.;D
Vest4		0.92
MutPred		0.72		Gain of catalytic residue at M239 (P = 0.0041);Gain of catalytic residue at M239 (P = 0.0041);
MVP		0.80
MPC		0.67
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.58
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs944282394; hg19: chr20-47686783;