rs145805814

Variant names:

• chr20-49063343-T-G
• rs145805814
• NM_001316.4:c.227T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001316.4(CSE1L):​c.227T>G​(p.Ile76Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000523 in 1,469,466 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense, splice_region
• Scores: Splicing: ADA: 0.9506
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10748559).
• BS2: High AC in GnomAd4 at 64 AD gene.

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.227T>G	p.Ile76Ser	missense splice_region	Exon 3 of 25	NP_001307.2
	CSE1L	NM_001362762.2		c.227T>G	p.Ile76Ser	missense splice_region	Exon 3 of 25	NP_001349691.1	P55060-3
	CSE1L	NM_001256135.2		c.227T>G	p.Ile76Ser	missense splice_region	Exon 3 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.227T>G	p.Ile76Ser	missense splice_region	Exon 3 of 25	ENSP00000262982.2	P55060-1
	CSE1L	ENST00000889064.1		c.227T>G	p.Ile76Ser	missense splice_region	Exon 4 of 26	ENSP00000559123.1
	CSE1L	ENST00000933032.1		c.227T>G	p.Ile76Ser	missense splice_region	Exon 3 of 25	ENSP00000603091.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000465 AC: 92 AN: 197832 AF XY: 0.000440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000534 AC: 704 AN: 1317300 Hom.: 0 Cov.: 22 AF XY: 0.000518 AC XY: 341 AN XY: 658712

African (AFR) AF: 0.0000715 AC: 2 AN: 27962

American (AMR) AF: 0.00113 AC: 32 AN: 28332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23082

East Asian (EAS) AF: 0.00 AC: 0 AN: 35962

South Asian (SAS) AF: 0.00 AC: 0 AN: 72082

European-Finnish (FIN) AF: 0.000196 AC: 10 AN: 51030

Middle Eastern (MID) AF: 0.000387 AC: 2 AN: 5162

European-Non Finnish (NFE) AF: 0.000624 AC: 636 AN: 1019126

Other (OTH) AF: 0.000403 AC: 22 AN: 54562

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74340

African (AFR) AF: 0.000145 AC: 6 AN: 41440

American (AMR) AF: 0.000524 AC: 8 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000429 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3476

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.26
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.011	D
Polyphen		0.032	B
Vest4		0.65
MVP		0.12
MPC		0.64
ClinPred		0.13	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.62
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.030		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: rs145805814; hg19: chr20-47679880;