chr5-10250342-T-G
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_012073.5(CCT5):āc.2T>Gā(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 34)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
CCT5
NM_012073.5 start_lost
NM_012073.5 start_lost
Scores
6
6
4
Clinical Significance
Conservation
PhyloP100: 7.24
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 Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCT5 | NM_012073.5 | c.2T>G | p.Met1? | start_lost | 1/11 | ENST00000280326.9 | |
CCT5 | NM_001306154.2 | c.2T>G | p.Met1? | start_lost | 1/10 | ||
CCT5 | NM_001306153.1 | c.42+297T>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCT5 | ENST00000280326.9 | c.2T>G | p.Met1? | start_lost | 1/11 | 1 | NM_012073.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251056Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135864
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461730Hom.: 0 Cov.: 37 AF XY: 0.00000825 AC XY: 6AN XY: 727156
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GnomAD4 genome Cov.: 34
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34
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 13, 2017 | The c.2T>G variant is predicted to cause a start-loss of the CCT5 gene due to a change of the methionine initiation codon. This variant has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. The connection of CCT5 and hereditary sensory neuropathy with spastic paraplegia (MIM: 256840) is poorly understood at the present time. The HGMD database reports a single variant, the p.H147R, where it was shown to segregate in one Moroccan family with four affected homozygote siblings (Bouhouche, 2006). Since then, a single unaffected homozygote individual with p.H147R variant was reported by the Saudi Human Genome Program in an effort to uncover rare benign variants (Abouelhoda, 2016). The c.2T>G variant is listed in the Genome Aggregation Database (gnomAD) observed on a single chromosome out of 246,066. Given our current understanding, there is not enough evidence to classify the c.2T>G variant with certainty. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Pathogenic
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
D;P;.
Vest4
MutPred
Gain of methylation at M1 (P = 0.0123);Gain of methylation at M1 (P = 0.0123);Gain of methylation at M1 (P = 0.0123);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
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