rs768671276

Variant names:

• chr5-10262617-A-C
• rs768671276
• NM_012073.5:c.1316A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012073.5(CCT5):​c.1316A>C​(p.Lys439Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CCT5 NM_012073.5 missense, splice_region
• Scores: Splicing: ADA: 0.8852
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33928883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCT5	NM_012073.5	c.1316A>C	p.Lys439Thr	missense_variant, splice_region_variant	Exon 9 of 11	ENST00000280326.9	NP_036205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCT5	ENST00000280326.9	c.1316A>C	p.Lys439Thr	missense_variant, splice_region_variant	Exon 9 of 11	1	NM_012073.5	ENSP00000280326.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251424 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135886

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727234

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory and autonomic neuropathy with spastic paraplegia Uncertain:1

May 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with CCT5-related disease. ClinVar contains an entry for this variant (Variation ID: 465406). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is present in population databases (rs768671276, ExAC 0.003%). This sequence change replaces lysine with threonine at codon 439 of the CCT5 protein (p.Lys439Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T
Polyphen		0.092	B;.;B;.;.
Vest4		0.54
MutPred		0.36		Loss of methylation at K439 (P = 0.0097);.;.;.;.;
MVP		0.49
MPC		0.42
ClinPred		0.73	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.63
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.14		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: rs768671276; hg19: chr5-10262729;