2-73252775-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006429.4(CCT7):c.1546G>A(p.Val516Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: CCT7 NM_006429.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

Genes affected

CCT7 (HGNC:1622): (chaperonin containing TCP1 subunit 7) 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. Related pseudogenes have been identified on chromosomes 5 and 6. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3756325).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCT7	NM_006429.4	c.1546G>A	p.Val516Ile	missense_variant	12/12	ENST00000258091.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCT7	ENST00000258091.10	c.1546G>A	p.Val516Ile	missense_variant	12/12	1	NM_006429.4	P1
CCT7	ENST00000539919.5	c.1414G>A	p.Val472Ile	missense_variant	13/13	2
CCT7	ENST00000540468.5	c.1285G>A	p.Val429Ile	missense_variant	10/10	2
CCT7	ENST00000398422.2	c.934G>A	p.Val312Ile	missense_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249558 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135408

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000579

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: 0.0000794

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

Dec 21, 2022

The c.1546G>A (p.V516I) alteration is located in exon 12 (coding exon 12) of the CCT7 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the valine (V) at amino acid position 516 to be replaced by an isoleucine (I). 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	Benign	0.14
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Benign	0.85
Eigen	Benign	0.057
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.73	N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.86	T;T;T;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.90	.;.;P;.
Vest4		0.38
MVP		0.53
MPC		0.39
ClinPred		0.090	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.78

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: rs369624680; hg19: chr2-73479903;