dbSNP rs904755375: CCT4:p.Thr342Ser (chr2-61873102-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006430.4(CCT4):c.1025C>G(p.Thr342Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T342N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CCT4
NM_006430.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.83

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCT4	NM_006430.4 link	c.1025C>G	p.Thr342Ser	missense_variant	Exon 10 of 14	ENST00000394440.8	NP_006421.2	P50991-1
CCT4	NM_001256721.1 link	c.935C>G	p.Thr312Ser	missense_variant	Exon 9 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.1025C>G	p.Thr342Ser	missense_variant	Exon 10 of 14	1	NM_006430.4	ENSP00000377958.3		P50991-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452860

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103850

Other (OTH)

AF:

0.00

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.0056

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;.

PhyloP100

7.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.020

N;N

REVEL

Benign

0.16

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.075

T;T

Polyphen

0.0010

B;.

Vest4

0.62

MutPred

0.70

Gain of glycosylation at T342 (P = 0.0746);.;

MVP

0.39

MPC

0.25

ClinPred

0.70

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.79

Mutation Taster

=75/25

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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rs904755375

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over