20-49070246-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_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
NM_001316.4 missense
Scores
10
6
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CSE1L
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.905
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSE1L | NM_001316.4 | c.717G>A | p.Met239Ile | missense_variant | 8/25 | ENST00000262982.3 | |
CSE1L | NM_001362762.2 | c.717G>A | p.Met239Ile | missense_variant | 8/25 | ||
CSE1L | NM_001256135.2 | c.717G>A | p.Met239Ile | missense_variant | 8/24 | ||
CSE1L | NR_045796.2 | n.355G>A | non_coding_transcript_exon_variant | 5/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSE1L | ENST00000262982.3 | c.717G>A | p.Met239Ile | missense_variant | 8/25 | 1 | NM_001316.4 | P1 | |
CSE1L | ENST00000396192.7 | c.717G>A | p.Met239Ile | missense_variant | 8/24 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000152 AC: 2AN: 1319574Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 660630
GnomAD4 exome
AF:
AC:
2
AN:
1319574
Hom.:
Cov.:
22
AF XY:
AC XY:
0
AN XY:
660630
Gnomad4 AFR exome
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Gnomad4 SAS exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Alfa
AF:
Hom.:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
T;T
Polyphen
0.99
.;D
Vest4
MutPred
Gain of catalytic residue at M239 (P = 0.0041);Gain of catalytic residue at M239 (P = 0.0041);
MVP
MPC
0.67
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -41
Find out detailed SpliceAI scores and Pangolin per-transcript scores at