chr1-156317541-T-C

Variant names:

• chr1-156317541-T-C
• rs2101640101
• NM_005998.5:c.766A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005998.5(CCT3):​c.766A>G​(p.Ile256Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCT3 NM_005998.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23
• Publications: 0 publications found

Genes affected

CCT3 (HGNC:1616): (chaperonin containing TCP1 subunit 3) The protein encoded by this gene is 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. Alternate transcriptional splice variants have been characterized for this gene. In addition, a pseudogene of this gene has been found on chromosome 8. [provided by RefSeq, Aug 2010]

CCT3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder with speech or visual impairment and brain hypomyelination

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15030995).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005998.5. 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
	CCT3	NM_005998.5	MANE Select	c.766A>G	p.Ile256Val	missense	Exon 9 of 14	NP_005989.3
	CCT3	NM_001008800.3		c.652A>G	p.Ile218Val	missense	Exon 7 of 12	NP_001008800.1	P49368-2
	CCT3	NR_036564.2		n.1036A>G		non_coding_transcript_exon	Exon 10 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT3	ENST00000295688.8	TSL:1 MANE Select	c.766A>G	p.Ile256Val	missense	Exon 9 of 14	ENSP00000295688.3	P49368-1
	CCT3	ENST00000954294.1		c.787A>G	p.Ile263Val	missense	Exon 9 of 14	ENSP00000624353.1
	CCT3	ENST00000898516.1		c.781A>G	p.Ile261Val	missense	Exon 9 of 14	ENSP00000568575.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460136 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110674

Other (OTH) AF: 0.00 AC: 0 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	Benign	0.12
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		6.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.069
Sift	Benign	0.59	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.34
MutPred		0.43		Loss of sheet (P = 0.1158)
MVP		0.15
MPC		0.23
ClinPred		0.57	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.38
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs2101640101; hg19: chr1-156287332;