21-29062506-G-T

Variant names:

• chr21-29062506-G-T
• rs1186589402
• NM_006585.4:c.992C>A

Variant summary

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

The NM_006585.4(CCT8):​c.992C>A​(p.Thr331Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,572 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. T331I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCT8 NM_006585.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.992C>A	p.Thr331Lys	missense	Exon 9 of 15	NP_006576.2
	CCT8	NM_001282907.2		c.935C>A	p.Thr312Lys	missense	Exon 10 of 16	NP_001269836.1	P50990-2
	CCT8	NM_001282908.2		c.839C>A	p.Thr280Lys	missense	Exon 9 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.992C>A	p.Thr331Lys	missense	Exon 9 of 15	ENSP00000286788.4	P50990-1
	CCT8	ENST00000470450.5	TSL:1	n.1066C>A		non_coding_transcript_exon	Exon 9 of 15
	CCT8	ENST00000936253.1		c.986C>A	p.Thr329Lys	missense	Exon 9 of 15	ENSP00000606312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461572 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111814

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.014	D
Sift4G	Benign	0.11	T
Polyphen		0.94	P
Vest4		0.46
MutPred		0.48		Gain of loop (P = 0.0312)
MVP		0.62
MPC		0.60
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.80
gMVP		0.73
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1186589402; hg19: chr21-30434827;