NM_012073.5:c.40C>T

Variant names:

• chr5-10250380-C-T
• NM_012073.5:c.40C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012073.5(CCT5):​c.40C>T​(p.Arg14Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CCT5 NM_012073.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy with spastic paraplegia

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012073.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	NM_012073.5	MANE Select	c.40C>T	p.Arg14Cys	missense	Exon 1 of 11	NP_036205.1	P48643-1
	CCT5	NM_001306154.2		c.40C>T	p.Arg14Cys	missense	Exon 1 of 10	NP_001293083.1	E7ENZ3
	CCT5	NM_001306153.1		c.42+335C>T		intron	N/A	NP_001293082.1	B4DX08

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	ENST00000280326.9	TSL:1 MANE Select	c.40C>T	p.Arg14Cys	missense	Exon 1 of 11	ENSP00000280326.4	P48643-1
	CCT5	ENST00000964556.1		c.40C>T	p.Arg14Cys	missense	Exon 1 of 11	ENSP00000634615.1
	CCT5	ENST00000964554.1		c.40C>T	p.Arg14Cys	missense	Exon 1 of 11	ENSP00000634613.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary sensory and autonomic neuropathy with spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.54		Loss of solvent accessibility (P = 0.0435)
MVP		0.53
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.074	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.67
gMVP		0.70
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

hg19: chr5-10250492;