21-29062213-A-G

Variant names:

• chr21-29062213-A-G
• rs142359495
• NM_006585.4:c.1127T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006585.4(CCT8):​c.1127T>C​(p.Val376Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V376G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCT8 NM_006585.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.62
• Publications: 0 publications found

Genes affected

CCT8 (HGNC:1623): (chaperonin containing TCP1 subunit 8) This gene encodes the theta subunit of the CCT chaperonin, which is abundant in the eukaryotic cytosol and may be involved in the transport and assembly of newly synthesized proteins. Alternative splicing results in multiple transcript variants of this gene. A pseudogene related to this gene is located on chromosome 1. [provided by RefSeq, Sep 2013]

CCT8 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006585.4. 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
	CCT8	NM_006585.4	MANE Select	c.1127T>C	p.Val376Ala	missense	Exon 11 of 15	NP_006576.2
	CCT8	NM_001282907.2		c.1070T>C	p.Val357Ala	missense	Exon 12 of 16	NP_001269836.1	P50990-2
	CCT8	NM_001282908.2		c.974T>C	p.Val325Ala	missense	Exon 11 of 15	NP_001269837.1	Q7Z759

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT8	ENST00000286788.9	TSL:1 MANE Select	c.1127T>C	p.Val376Ala	missense	Exon 11 of 15	ENSP00000286788.4	P50990-1
	CCT8	ENST00000470450.5	TSL:1	n.1201T>C		non_coding_transcript_exon	Exon 11 of 15
	CCT8	ENST00000936253.1		c.1121T>C	p.Val374Ala	missense	Exon 11 of 15	ENSP00000606312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461524 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111800

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.013	D
Polyphen		0.51	P
Vest4		0.72
MutPred		0.79		Loss of stability (P = 0.0594)
MVP		0.44
MPC		0.23
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.74
Mutation Taster		=37/63	disease causing

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: rs142359495; hg19: chr21-30434534;