5-10250342-T-G

Position:

• chr5-10250342-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_012073.5(CCT5):​c.2T>G​(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 (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CCT5 NM_012073.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

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 exomes AF: 0.00000398 AC: 1 AN: 251056 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

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

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

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: 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

Other links and lift over

dbSNP: rs1355388433; hg19: chr5-10250454;