5-36177202-A-C

Variant summary

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

The NM_005983.4(SKP2):​c.971A>C​(p.Lys324Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SKP2
NM_005983.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93
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=0.14773872).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SKP2NM_005983.4 linkuse as main transcriptc.971A>C p.Lys324Thr missense_variant 9/10 ENST00000274255.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SKP2ENST00000274255.11 linkuse as main transcriptc.971A>C p.Lys324Thr missense_variant 9/101 NM_005983.4 P1Q13309-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

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 GeneticsNov 08, 2022The c.971A>C (p.K324T) alteration is located in exon 9 (coding exon 9) of the SKP2 gene. This alteration results from a A to C substitution at nucleotide position 971, causing the lysine (K) at amino acid position 324 to be replaced by a threonine (T). 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
0.19
BayesDel_addAF
Benign
-0.090
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
19
DANN
Benign
0.74
DEOGEN2
Benign
0.12
.;.;T;T;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.44
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.84
T;T;T;T;T
M_CAP
Benign
0.0065
T
MetaRNN
Benign
0.15
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.080
N;.;N;.;.
MutationTaster
Benign
0.78
D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Benign
2.8
N;.;N;.;N
REVEL
Benign
0.21
Sift
Benign
1.0
T;.;T;.;T
Sift4G
Benign
0.53
T;T;T;T;T
Polyphen
0.014
B;.;B;.;.
Vest4
0.39
MutPred
0.67
Loss of solvent accessibility (P = 0.0045);.;Loss of solvent accessibility (P = 0.0045);.;.;
MVP
0.46
MPC
0.58
ClinPred
0.97
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.20
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: chr5-36177304; API