rs146765948

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006430.4(CCT4):c.1448G>A(p.Arg483Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000842 in 1,613,854 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 2 hom. )

Consequence

CCT4
NM_006430.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 4.97

Publications

3 publications found

Variant links:

Genes affected

CCT4 (HGNC:1617): (chaperonin containing TCP1 subunit 4) The chaperonin containing TCP1 (MIM 186980) complex (CCT), also called the TCP1 ring complex, consists of 2 back-to-back rings, each containing 8 unique but homologous subunits, such as CCT4. CCT assists the folding of newly translated polypeptide substrates through multiple rounds of ATP-driven release and rebinding of partially folded intermediate forms. Substrates of CCT include the cytoskeletal proteins actin (see MIM 102560) and tubulin (see MIM 191130), as well as alpha-transducin (MIM 139330) (Won et al., 1998 [PubMed 9819444]).[supplied by OMIM, Mar 2008]

CCT4 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CCT4 links:

ENSG00000236498 (HGNC:):

ENSG00000236498 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057412773).

BS2

High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCT4	NM_006430.4 link	c.1448G>A	p.Arg483Gln	missense_variant	Exon 12 of 14	ENST00000394440.8	NP_006421.2	P50991-1
CCT4	NM_001256721.1 link	c.1358G>A	p.Arg453Gln	missense_variant	Exon 11 of 13		NP_001243650.1	P50991-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCT4	ENST00000394440.8 link	c.1448G>A	p.Arg483Gln	missense_variant	Exon 12 of 14	1	NM_006430.4	ENSP00000377958.3		P50991-1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000815

AC:

205

AN:

251402

AF XY:

0.000817

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000985

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000863

AC:

1261

AN:

1461622

Hom.:

Cov.:

AF XY:

0.000883

AC XY:

642

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33476

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00467

AC:

122

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.000406

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.0162

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.000795

AC:

884

AN:

1111894

Other (OTH)

AF:

0.00154

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000644

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41518

American (AMR)

AF:

0.000458

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000793

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000708

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000764

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1448G>A (p.R483Q) alteration is located in exon 12 (coding exon 12) of the CCT4 gene. This alteration results from a G to A substitution at nucleotide position 1448, causing the arginine (R) at amino acid position 483 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CCT4-related disorder

Benign:1

Feb 03, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.7

L;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.054

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.33

B;.

Vest4

0.78

MVP

0.62

MPC

0.53

ClinPred

0.075

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.73

Mutation Taster

=80/20

polymorphism

(source)

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

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rs146765948

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over