20-49063343-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSE1L	NM_001316.4	c.227T>G	p.Ile76Ser	missense_variant, splice_region_variant	Exon 3 of 25	ENST00000262982.3	NP_001307.2
CSE1L	NM_001362762.2	c.227T>G	p.Ile76Ser	missense_variant, splice_region_variant	Exon 3 of 25		NP_001349691.1
CSE1L	NM_001256135.2	c.227T>G	p.Ile76Ser	missense_variant, splice_region_variant	Exon 3 of 24		NP_001243064.1
CSE1L	NR_045796.2	n.300+50T>G		intron_variant	Intron 3 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSE1L	ENST00000262982.3	c.227T>G	p.Ile76Ser	missense_variant, splice_region_variant	Exon 3 of 25	1	NM_001316.4	ENSP00000262982.2
CSE1L	ENST00000396192.7	c.227T>G	p.Ile76Ser	missense_variant, splice_region_variant	Exon 3 of 24	5		ENSP00000379495.3

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

GnomAD3 exomes AF: 0.000465 AC: 92 AN: 197832 Hom.: 0 AF XY: 0.000440 AC XY: 48 AN XY: 109120

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 SAS 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

Gnomad4 AFR exome AF: 0.0000715

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000196

Gnomad4 NFE exome AF: 0.000624

Gnomad4 OTH exome AF: 0.000403

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

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000337 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.227T>G (p.I76S) alteration is located in exon 3 (coding exon 2) of the CSE1L gene. This alteration results from a T to G substitution at nucleotide position 227, causing the isoleucine (I) at amino acid position 76 to be replaced by a serine (S). 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	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;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.26
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.011	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs145805814; hg19: chr20-47679880;