20-49070216-A-T

Variant names:

• chr20-49070216-A-T
• rs983157560
• NM_001316.4:c.687A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_001316.4(CSE1L):​c.687A>T​(p.Glu229Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000389 in 1,284,434 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: 0.0000039 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.462
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• BS2: High AC in GnomAdExome4 at 5 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.687A>T	p.Glu229Asp	missense	Exon 8 of 25	NP_001307.2
	CSE1L	NM_001362762.2		c.687A>T	p.Glu229Asp	missense	Exon 8 of 25	NP_001349691.1	P55060-3
	CSE1L	NM_001256135.2		c.687A>T	p.Glu229Asp	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.687A>T	p.Glu229Asp	missense	Exon 8 of 25	ENSP00000262982.2	P55060-1
	CSE1L	ENST00000889064.1		c.687A>T	p.Glu229Asp	missense	Exon 9 of 26	ENSP00000559123.1
	CSE1L	ENST00000933032.1		c.687A>T	p.Glu229Asp	missense	Exon 8 of 25	ENSP00000603091.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000389 AC: 5 AN: 1284434 Hom.: 0 Cov.: 20 AF XY: 0.00000465 AC XY: 3 AN XY: 644732

African (AFR) AF: 0.00 AC: 0 AN: 28456

American (AMR) AF: 0.00 AC: 0 AN: 34438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24066

East Asian (EAS) AF: 0.00 AC: 0 AN: 37654

South Asian (SAS) AF: 0.00 AC: 0 AN: 73824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.00000514 AC: 5 AN: 973694

Other (OTH) AF: 0.00 AC: 0 AN: 54152

GnomAD4 genome Cov.: 33

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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.46
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.49
Sift	Benign	0.043	D
Sift4G	Benign	0.064	T
Polyphen		0.86	P
Vest4		0.75
MutPred		0.79		Gain of helix (P = 0.1736)
MVP		0.57
MPC		0.53
ClinPred		0.97	D
GERP RS		-0.96
Varity_R		0.41
gMVP		0.45
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs983157560; hg19: chr20-47686753;