rs118203986
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_012073.5(CCT5):āc.440A>Gā(p.His147Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000979 in 1,614,144 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 (ā ā ).
Frequency
Genomes: š 0.00040 ( 0 hom., cov: 33)
Exomes š: 0.000066 ( 0 hom. )
Consequence
CCT5
NM_012073.5 missense
NM_012073.5 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 7.06
Genes affected
CCT5 (HGNC:1618): (chaperonin containing TCP1 subunit 5) The protein encoded by this gene is a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). This complex consists of two identical stacked rings, each containing eight different proteins. Unfolded polypeptides enter the central cavity of the complex and are folded in an ATP-dependent manner. The complex folds various proteins, including actin and tubulin. Mutations in this gene cause hereditary sensory and autonomic neuropathy with spastic paraplegia (HSNSP). Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 5 and 13. [provided by RefSeq, Apr 2015]
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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=0.071017474).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCT5 | NM_012073.5 | c.440A>G | p.His147Arg | missense_variant | 4/11 | ENST00000280326.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCT5 | ENST00000280326.9 | c.440A>G | p.His147Arg | missense_variant | 4/11 | 1 | NM_012073.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152234Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251374Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135854
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GnomAD4 exome AF: 0.0000664 AC: 97AN: 1461792Hom.: 0 Cov.: 35 AF XY: 0.0000674 AC XY: 49AN XY: 727190
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GnomAD4 genome ? AF: 0.000400 AC: 61AN: 152352Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26AN XY: 74516
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary sensory and autonomic neuropathy with spastic paraplegia Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 147 of the CCT5 protein (p.His147Arg). This variant is present in population databases (rs118203986, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mutilating sensory neuropathy with spastic paraplegia (PMID: 16399879). ClinVar contains an entry for this variant (Variation ID: 1327). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CCT5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CCT5 function (PMID: 25124038, 25345891, 28623285, 29552646). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2006 | - - |
not provided Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | GeneDx | Oct 06, 2016 | The H147R variant in the CCT5 gene has been reported previously in the homozygous state in four brothers with mutilating sensory neuropathy and spastic paraplegia (Bouhouche et al., 2006). The H147R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H147R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret H147R as a likely pathogenic variant, - |
CCT5-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2024 | The CCT5 c.440A>G variant is predicted to result in the amino acid substitution p.His147Arg. This variant has been reported in the homozygous state in multiple family members with neuropathy and spastic paraplegia (Figure 1, Bouhouche et al. 2006. PubMed ID: 16399879). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. The results of in vitro experimental studies of this variant are inconclusive (Sergeeva et al. 2014. PubMed ID: 25124038; Min et al. 2014. PubMed ID: 25345891; Pereira et al. 2017. PubMed ID: 28623285; Spigolon et al. 2017. PubMed ID: 29552646). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.;.
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
B;.;B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at