17-63831415-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002805.6(PSMC5):​c.959C>G​(p.Pro320Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

PSMC5
NM_002805.6 missense

Scores

16
2
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
PSMC5 (HGNC:9552): (proteasome 26S subunit, ATPase 5) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown to interact with the thyroid hormone receptor and retinoid X receptor-alpha. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PSMC5NM_002805.6 linkc.959C>G p.Pro320Arg missense_variant Exon 9 of 12 ENST00000310144.11 NP_002796.4 P62195-1A0A140VJS3
PSMC5NM_001199163.2 linkc.935C>G p.Pro312Arg missense_variant Exon 9 of 12 NP_001186092.1 P62195-2
PSMC5XM_047436423.1 linkc.*256C>G downstream_gene_variant XP_047292379.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PSMC5ENST00000310144.11 linkc.959C>G p.Pro320Arg missense_variant Exon 9 of 12 1 NM_002805.6 ENSP00000310572.6 P62195-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 15, 2025
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;.;D;.
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.2
H;.;.;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-8.2
D;.;D;.
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.87
MutPred
0.86
Loss of glycosylation at P320 (P = 0.0211);.;.;.;
MVP
0.90
MPC
1.8
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.99
gMVP
1.0

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: chr17-61908775; API