20-49066193-T-C

Position:

• chr20-49066193-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001316.4(CSE1L):​c.230T>C​(p.Val77Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense, splice_region
• Scores: Splicing: ADA: 0.1899
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17200992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.230T>C	p.Val77Ala	missense_variant, splice_region_variant	4/25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.230T>C	p.Val77Ala	missense_variant, splice_region_variant	4/25		NP_001349691.1
CSE1L	NM_001256135.2	c.230T>C	p.Val77Ala	missense_variant, splice_region_variant	4/24		NP_001243064.1
CSE1L	NR_045796.2	n.301-2617T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.230T>C	p.Val77Ala	missense_variant, splice_region_variant	4/25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.230T>C	p.Val77Ala	missense_variant, splice_region_variant	4/24	5		ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251204 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461670 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Jul 17, 2024

The c.230T>C (p.V77A) alteration is located in exon 4 (coding exon 3) of the CSE1L gene. This alteration results from a T to C substitution at nucleotide position 230, causing the valine (V) at amino acid position 77 to be replaced by an alanine (A). 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	0.15
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.098
Sift	Benign	0.75	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.064	.;B
Vest4		0.47
MutPred		0.40		Loss of MoRF binding (P = 0.115);Loss of MoRF binding (P = 0.115);
MVP		0.068
MPC		0.57
ClinPred		0.39	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: -19

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

Publications

LitVar

Other links and lift over

dbSNP: rs200581090; hg19: chr20-47682730;