rs118203986

Positions:

chr5-10256063-A-G

Variant summary

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

The NM_012073.5(CCT5):c.440A>G(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 (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

CCT5
NM_012073.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 7.06

Variant links:

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]

CCT5 links:

CCT5 (HGNC:):

CCT5 links:

Genome browser will be placed here

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	Protein	UniProt
CCT5	NM_012073.5 linkuse as main transcript	c.440A>G	p.His147Arg	missense_variant	4/11	ENST00000280326.9	NP_036205.1	P48643-1V9HW37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCT5	ENST00000280326.9 linkuse as main transcript	c.440A>G	p.His147Arg	missense_variant	4/11	1	NM_012073.5	ENSP00000280326.4		P48643-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

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:

0.0000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251374

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

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:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000671

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:

0.0000279

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000400

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -
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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2024

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 is observed in 21/34414 (0.06%) alleles from individuals of Latino background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The H147R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In vitro assays demonstrated that although H147R did not cause a major defect in chaperonin structure and hydrolyzed ATP with similar efficiency to the wild type cells, H147R transfected cells showed a significant reduction in chaperone activity (Sergeeva et al., 2014). We interpret H147R as a likely pathogenic variant. -

CCT5-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

T;.;.;T;.

Eigen

Benign

-0.068

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.071

T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.16

N;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.51

T;T;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.0010

B;.;B;.;.

Vest4

0.76

MVP

0.69

MPC

0.40

ClinPred

0.033

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.59

gMVP

0.69

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over