chr2-61872086-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_006430.4(CCT4):c.1487G>A(p.Arg496Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,594,000 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: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CCT4
NM_006430.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83

Publications

6 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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCT4	NM_006430.4 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 12 of 14	ENST00000394440.8	NP_006421.2	P50991-1
CCT4	NM_001256721.1 link	c.1397G>A	p.Arg466Gln	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.1487G>A	p.Arg496Gln	missense_variant	Exon 12 of 14	1	NM_006430.4	ENSP00000377958.3		P50991-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250904

AF XY:

0.0000369

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1441836

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

718612

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33054

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.000163

AC:

AN:

85738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5060

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1094738

Other (OTH)

AF:

0.0000168

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1487G>A (p.R496Q) 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 1487, causing the arginine (R) at amino acid position 496 to be replaced by a glutamine (Q). 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

0.60

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.61

Sift

Benign

0.031

D;D

Sift4G

Benign

0.27

T;T

Polyphen

1.0

D;.

Vest4

0.82

MVP

0.71

MPC

0.93

ClinPred

0.89

GERP RS

5.6

Varity_R

0.80

gMVP

0.66

Mutation Taster

=9/91

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr2-61872086-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over