5-36152839-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005983.4(SKP2):​c.77C>T​(p.Ser26Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,938 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: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SKP2
NM_005983.4 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16069508).
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SKP2NM_005983.4 linkuse as main transcriptc.77C>T p.Ser26Phe missense_variant 2/10 ENST00000274255.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SKP2ENST00000274255.11 linkuse as main transcriptc.77C>T p.Ser26Phe missense_variant 2/101 NM_005983.4 P1Q13309-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251458
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
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:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000120
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.00000824
AC:
1

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 GeneticsAug 02, 2023The c.77C>T (p.S26F) alteration is located in exon 2 (coding exon 2) of the SKP2 gene. This alteration results from a C to T substitution at nucleotide position 77, causing the serine (S) at amino acid position 26 to be replaced by a phenylalanine (F). 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
0.20
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
.;T;T;.;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Benign
0.56
D
LIST_S2
Uncertain
0.93
D;D;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.16
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L;L;.;.;.
MutationTaster
Benign
0.94
D;D;D;N
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-2.6
D;D;.;N;N
REVEL
Benign
0.078
Sift
Uncertain
0.0070
D;D;.;D;D
Sift4G
Uncertain
0.017
D;D;D;T;D
Polyphen
0.99
D;P;.;.;.
Vest4
0.23
MutPred
0.31
Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);.;Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);
MVP
0.17
MPC
1.0
ClinPred
0.78
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.29
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs774666099; hg19: chr5-36152941; API