20-49070232-A-G

Variant names:

• chr20-49070232-A-G
• rs1290509499
• NM_001316.4:c.703A>G

Variant summary

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

The NM_001316.4(CSE1L):​c.703A>G​(p.Met235Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,314,514 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: 0.0000030 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.01

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.703A>G	p.Met235Val	missense_variant	Exon 8 of 25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.703A>G	p.Met235Val	missense_variant	Exon 8 of 25		NP_001349691.1
CSE1L	NM_001256135.2	c.703A>G	p.Met235Val	missense_variant	Exon 8 of 24		NP_001243064.1
CSE1L	NR_045796.2	n.341A>G		non_coding_transcript_exon_variant	Exon 5 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.703A>G	p.Met235Val	missense_variant	Exon 8 of 25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.703A>G	p.Met235Val	missense_variant	Exon 8 of 24	5		ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000304 AC: 4 AN: 1314514 Hom.: 0 Cov.: 22 AF XY: 0.00000456 AC XY: 3 AN XY: 658586

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: 0.00000401

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703A>G (p.M235V) alteration is located in exon 8 (coding exon 7) of the CSE1L gene. This alteration results from a A to G substitution at nucleotide position 703, causing the methionine (M) at amino acid position 235 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	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	.;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.58
Sift	Benign	0.28	T;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.97	.;D
Vest4		0.84
MutPred		0.68		Gain of catalytic residue at M235 (P = 0.0047);Gain of catalytic residue at M235 (P = 0.0047);
MVP		0.72
MPC		0.48
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1290509499; hg19: chr20-47686769;