chr20-49063222-G-A

Position:

• chr20-49063222-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001316.4(CSE1L):​c.106G>A​(p.Val36Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,430,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CSE1L NM_001316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

CSE1L (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3130175).
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.106G>A	p.Val36Ile	missense_variant	3/25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.106G>A	p.Val36Ile	missense_variant	3/25		NP_001349691.1
CSE1L	NM_001256135.2	c.106G>A	p.Val36Ile	missense_variant	3/24		NP_001243064.1
CSE1L	NR_045796.2	n.229G>A		non_coding_transcript_exon_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.106G>A	p.Val36Ile	missense_variant	3/25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.106G>A	p.Val36Ile	missense_variant	3/24	5		ENSP00000379495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000203 AC: 29 AN: 1430720 Hom.: 0 Cov.: 28 AF XY: 0.0000140 AC XY: 10 AN XY: 711812

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: 0.0000263

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 19, 2024

The c.106G>A (p.V36I) alteration is located in exon 3 (coding exon 2) of the CSE1L gene. This alteration results from a G to A substitution at nucleotide position 106, causing the valine (V) at amino acid position 36 to be replaced by an isoleucine (I). 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	0.096
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.54	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.31	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.62	.;P
Vest4		0.39
MutPred		0.40		Loss of ubiquitination at K31 (P = 0.1);Loss of ubiquitination at K31 (P = 0.1);
MVP		0.48
MPC		0.45
ClinPred		0.67	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2091865760; hg19: chr20-47679759;