20-49070218-T-A

Variant names:

• chr20-49070218-T-A
• rs912785951
• NM_001316.4:c.689T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001316.4(CSE1L):​c.689T>A​(p.Phe230Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,240 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSE1L	NM_001316.4	MANE Select	c.689T>A	p.Phe230Tyr	missense	Exon 8 of 25	NP_001307.2
	CSE1L	NM_001362762.2		c.689T>A	p.Phe230Tyr	missense	Exon 8 of 25	NP_001349691.1	P55060-3
	CSE1L	NM_001256135.2		c.689T>A	p.Phe230Tyr	missense	Exon 8 of 24	NP_001243064.1	P55060-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSE1L	ENST00000262982.3	TSL:1 MANE Select	c.689T>A	p.Phe230Tyr	missense	Exon 8 of 25	ENSP00000262982.2	P55060-1
	CSE1L	ENST00000889064.1		c.689T>A	p.Phe230Tyr	missense	Exon 9 of 26	ENSP00000559123.1
	CSE1L	ENST00000933032.1		c.689T>A	p.Phe230Tyr	missense	Exon 8 of 25	ENSP00000603091.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000450 AC: 1 AN: 221988 AF XY: 0.00000830

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1297016 Hom.: 0 Cov.: 20 AF XY: 0.00000154 AC XY: 1 AN XY: 650534

African (AFR) AF: 0.0000347 AC: 1 AN: 28828

American (AMR) AF: 0.00 AC: 0 AN: 34844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24172

East Asian (EAS) AF: 0.00 AC: 0 AN: 37912

South Asian (SAS) AF: 0.00 AC: 0 AN: 74416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 984098

Other (OTH) AF: 0.00 AC: 0 AN: 54564

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.0000482 AC: 2 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.79		Loss of stability (P = 0.0438)
MVP		0.45
MPC		0.61
ClinPred		0.58	D
GERP RS		5.4
Varity_R		0.58
gMVP		0.46
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs912785951; hg19: chr20-47686755;