20-49070216-A-T

Position:

• chr20-49070216-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP2 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

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CSE1L
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSE1L	NM_001316.4	c.687A>T	p.Glu229Asp	missense_variant	8/25	ENST00000262982.3
CSE1L	NM_001362762.2	c.687A>T	p.Glu229Asp	missense_variant	8/25
CSE1L	NM_001256135.2	c.687A>T	p.Glu229Asp	missense_variant	8/24
CSE1L	NR_045796.2	n.325A>T		non_coding_transcript_exon_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSE1L	ENST00000262982.3	c.687A>T	p.Glu229Asp	missense_variant	8/25	1	NM_001316.4	P1
CSE1L	ENST00000396192.7	c.687A>T	p.Glu229Asp	missense_variant	8/24	5

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

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: 0.00000514

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.687A>T (p.E229D) alteration is located in exon 8 (coding exon 7) of the CSE1L gene. This alteration results from a A to T substitution at nucleotide position 687, causing the glutamic acid (E) at amino acid position 229 to be replaced by an aspartic acid (D). 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.49
Sift	Benign	0.043	D;T
Sift4G	Benign	0.064	T;T
Polyphen		0.86	.;P
Vest4		0.75
MutPred		0.79		Gain of helix (P = 0.1736);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-47686753;