rs11557649

Positions:

• chr5-10258400-G-A
• chr5-10258400-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012073.5(CCT5):​c.738G>A​(p.Ala246=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,614,096 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A246A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (73 hom., cov: 33)
  • Exomes 𝑓: 0.033 (927 hom.)
• Consequence: CCT5 NM_012073.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.23

Genes affected

CCT5 (HGNC:1618): (chaperonin containing TCP1 subunit 5) 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. Mutations in this gene cause hereditary sensory and autonomic neuropathy with spastic paraplegia (HSNSP). Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 5 and 13. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-10258400-G-A is Benign according to our data. Variant chr5-10258400-G-A is described in ClinVar as [Benign]. Clinvar id is 240841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-10258400-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4187/152276) while in subpopulation NFE AF= 0.0399 (2716/68032). AF 95% confidence interval is 0.0387. There are 73 homozygotes in gnomad4. There are 2080 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCT5	NM_012073.5	c.738G>A	p.Ala246=	synonymous_variant	6/11	ENST00000280326.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCT5	ENST00000280326.9	c.738G>A	p.Ala246=	synonymous_variant	6/11	1	NM_012073.5	P1

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4186 AN: 152158 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.00579

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.00307

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0592

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0273 AC: 6866 AN: 251472 Hom.: 136 AF XY: 0.0276 AC XY: 3755 AN XY: 135916

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0397

Gnomad EAS exome AF: 0.00391

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0541

Gnomad NFE exome AF: 0.0355

Gnomad OTH exome AF: 0.0306

GnomAD4 exome AF: 0.0329 AC: 48047 AN: 1461820 Hom.: 927 Cov.: 33 AF XY: 0.0325 AC XY: 23660 AN XY: 727228

Gnomad4 AFR exome AF: 0.00430

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.0382

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0555

Gnomad4 NFE exome AF: 0.0362

Gnomad4 OTH exome AF: 0.0301

GnomAD4 genome AF: 0.0275 AC: 4187 AN: 152276 Hom.: 73 Cov.: 33 AF XY: 0.0279 AC XY: 2080 AN XY: 74448

Gnomad4 AFR AF: 0.00578

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0592

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0303 Hom.: 43

Bravo AF: 0.0229

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0333

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory and autonomic neuropathy with spastic paraplegia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.6
DANN	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs11557649; hg19: chr5-10258512;