chr17-34931051-C-A

Variant names:

• chr17-34931051-C-A
• rs770681410
• NM_006584.4:c.1348G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_006584.4(CCT6B):​c.1348G>T​(p.Val450Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000128 in 1,249,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CCT6B NM_006584.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006584.4. 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
	CCT6B	NM_006584.4	MANE Select	c.1348G>T	p.Val450Phe	missense splice_region	Exon 12 of 14	NP_006575.2	Q92526-1
	CCT6B	NM_001193529.3		c.1237G>T	p.Val413Phe	missense splice_region	Exon 11 of 13	NP_001180458.1	Q92526-3
	CCT6B	NM_001193530.2		c.1213G>T	p.Val405Phe	missense splice_region	Exon 11 of 13	NP_001180459.1	Q92526-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT6B	ENST00000314144.10	TSL:1 MANE Select	c.1348G>T	p.Val450Phe	missense splice_region	Exon 12 of 14	ENSP00000327191.5	Q92526-1
	CCT6B	ENST00000421975.7	TSL:1	c.1237G>T	p.Val413Phe	missense splice_region	Exon 11 of 13	ENSP00000398044.3	Q92526-3
	CCT6B	ENST00000436961.7	TSL:2	c.1213G>T	p.Val405Phe	missense splice_region	Exon 11 of 13	ENSP00000400917.3	Q92526-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000256 AC: 6 AN: 234702 AF XY: 0.0000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000300

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 16 AN: 1249462 Hom.: 0 Cov.: 18 AF XY: 0.0000112 AC XY: 7 AN XY: 625736

African (AFR) AF: 0.00 AC: 0 AN: 29282

American (AMR) AF: 0.0000248 AC: 1 AN: 40280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22664

East Asian (EAS) AF: 0.000294 AC: 11 AN: 37386

South Asian (SAS) AF: 0.00 AC: 0 AN: 65096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5098

European-Non Finnish (NFE) AF: 0.00000315 AC: 3 AN: 950982

Other (OTH) AF: 0.0000194 AC: 1 AN: 51604

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.85
MutPred		0.68		Gain of helix (P = 0.2059)
MVP		0.90
MPC		0.46
ClinPred		0.89	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.83
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.080		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

dbSNP: rs770681410; hg19: chr17-33258070;