chr5-10250342-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_012073.5(CCT5):ā€‹c.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

Scores

6
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.24
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]

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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
CCT5NM_012073.5 linkuse as main transcriptc.2T>G p.Met1? start_lost 1/11 ENST00000280326.9
CCT5NM_001306154.2 linkuse as main transcriptc.2T>G p.Met1? start_lost 1/10
CCT5NM_001306153.1 linkuse as main transcriptc.42+297T>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CCT5ENST00000280326.9 linkuse as main transcriptc.2T>G p.Met1? start_lost 1/111 NM_012073.5 P1P48643-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251056
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461730
Hom.:
0
Cov.:
37
AF XY:
0.00000825
AC XY:
6
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 13, 2017The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.15
T;.;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Benign
-0.36
T
MutationTaster
Benign
0.99
D;D;D
PROVEAN
Benign
-0.28
N;N;.
REVEL
Uncertain
0.41
Sift
Pathogenic
0.0
D;D;.
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
0.97
D;P;.
Vest4
0.93
MutPred
0.99
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
0.63
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.98
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1355388433; hg19: chr5-10250454; API