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GeneBe

5-36182022-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005983.4(SKP2):​c.1266T>A​(p.Ser422Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SKP2
NM_005983.4 missense

Scores

2
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0530
Variant links:
Genes affected
SKP2 (HGNC:10901): (S-phase kinase associated protein 2) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class; in addition to an F-box, this protein contains 10 tandem leucine-rich repeats. This protein is an essential element of the cyclin A-CDK2 S-phase kinase. It specifically recognizes phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B, also referred to as p27 or KIP1) predominantly in S phase and interacts with S-phase kinase-associated protein 1 (SKP1 or p19). In addition, this gene is established as a protooncogene causally involved in the pathogenesis of lymphomas. Alternative splicing of this gene generates three transcript variants encoding different isoforms. [provided by RefSeq, Jul 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09188068).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SKP2NM_005983.4 linkuse as main transcriptc.1266T>A p.Ser422Arg missense_variant 10/10 ENST00000274255.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SKP2ENST00000274255.11 linkuse as main transcriptc.1266T>A p.Ser422Arg missense_variant 10/101 NM_005983.4 P1Q13309-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 16, 2021The c.1266T>A (p.S422R) alteration is located in exon 10 (coding exon 10) of the SKP2 gene. This alteration results from a T to A substitution at nucleotide position 1266, causing the serine (S) at amino acid position 422 to be replaced by an arginine (R). 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
0.32
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
16
DANN
Uncertain
0.99
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.38
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.69
T;T;T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.092
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.33
T
Sift4G
Benign
0.40
T;T;T;T
Polyphen
0.18
.;B;.;.
Vest4
0.25
MutPred
0.29
.;Gain of MoRF binding (P = 5e-04);.;.;
MVP
0.32
MPC
0.55
ClinPred
0.25
T
GERP RS
0.87
Varity_R
0.075
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: chr5-36182124; API