Genetic Variant CCT6B:p.Gly329Asp (chr17-34939696-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006584.4(CCT6B):c.986G>A(p.Gly329Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,459,890 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: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CCT6B
NM_006584.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

Variant links:

Genes affected

CCT6B (HGNC:1621): (chaperonin containing TCP1 subunit 6B) This gene encodes 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

CCT6B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCT6B	NM_006584.4 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 9 of 14	ENST00000314144.10	NP_006575.2	Q92526-1
CCT6B	NM_001193529.3 link	c.875G>A	p.Gly292Asp	missense_variant	Exon 8 of 13		NP_001180458.1	Q92526-3
CCT6B	NM_001193530.2 link	c.851G>A	p.Gly284Asp	missense_variant	Exon 8 of 13		NP_001180459.1	Q92526-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCT6B	ENST00000314144.10 link	c.986G>A	p.Gly329Asp	missense_variant	Exon 9 of 14	1	NM_006584.4	ENSP00000327191.5	Q92526-1
CCT6B	ENST00000421975.7 link	c.875G>A	p.Gly292Asp	missense_variant	Exon 8 of 13	1		ENSP00000398044.3	Q92526-3
CCT6B	ENST00000436961.7 link	c.851G>A	p.Gly284Asp	missense_variant	Exon 8 of 13	2		ENSP00000400917.3	Q92526-2
CCT6B	ENST00000577307.1 link	n.2342G>A		non_coding_transcript_exon_variant	Exon 4 of 8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251140

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135734

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:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1459890

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726390

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000882

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.986G>A (p.G329D) alteration is located in exon 9 (coding exon 9) of the CCT6B gene. This alteration results from a G to A substitution at nucleotide position 986, causing the glycine (G) at amino acid position 329 to be replaced by an aspartic acid (D). 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

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.8

.;H;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.6

D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.90

MutPred

0.90

.;Gain of relative solvent accessibility (P = 0.0215);.;

MVP

0.90

MPC

0.48

ClinPred

0.98

GERP RS

4.7

Varity_R

0.89

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over