21-29063433-C-A

Position:

• chr21-29063433-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006585.4(CCT8):​c.860G>T​(p.Gly287Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
• Consequence: CCT8 NM_006585.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

Genes affected

CCT8 (HGNC:1623): (chaperonin containing TCP1 subunit 8) This gene encodes the theta subunit of the CCT chaperonin, which is abundant in the eukaryotic cytosol and may be involved in the transport and assembly of newly synthesized proteins. Alternative splicing results in multiple transcript variants of this gene. A pseudogene related to this gene is located on chromosome 1. [provided by RefSeq, Sep 2013]

CCT8 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCT8	NM_006585.4	c.860G>T	p.Gly287Val	missense_variant	8/15	ENST00000286788.9	NP_006576.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCT8	ENST00000286788.9	c.860G>T	p.Gly287Val	missense_variant	8/15	1	NM_006585.4	ENSP00000286788.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.860G>T (p.G287V) alteration is located in exon 8 (coding exon 8) of the CCT8 gene. This alteration results from a G to T substitution at nucleotide position 860, causing the glycine (G) at amino acid position 287 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.0	.;H;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-9.0	D;D;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.93
MutPred		0.87		.;Gain of sheet (P = 0.1208);.;
MVP		0.80
MPC		0.76
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs2085585885; hg19: chr21-30435754;