5-10250318-G-A

Position:

• chr5-10250318-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012073.5(CCT5):​c.-23G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,613,564 control chromosomes in the GnomAD database, including 555,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43669 hom., cov: 33)
  • Exomes 𝑓: 0.83 (512317 hom.)
• Consequence: CCT5 NM_012073.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.574

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-10250318-G-A is Benign according to our data. Variant chr5-10250318-G-A is described in ClinVar as [Benign]. Clinvar id is 350245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-10250318-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCT5	NM_012073.5	c.-23G>A		5_prime_UTR_variant	1/11	ENST00000280326.9
CCT5	NM_001306154.2	c.-23G>A		5_prime_UTR_variant	1/10
CCT5	NM_001306153.1	c.42+273G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCT5	ENST00000280326.9	c.-23G>A		5_prime_UTR_variant	1/11	1	NM_012073.5	P1

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112271 AN: 152072 Hom.: 43652 Cov.: 33

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.766

GnomAD3 exomes AF: 0.799 AC: 199959 AN: 250370 Hom.: 81494 AF XY: 0.799 AC XY: 108338 AN XY: 135586

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.802

Gnomad ASJ exome AF: 0.868

Gnomad EAS exome AF: 0.863

Gnomad SAS exome AF: 0.665

Gnomad FIN exome AF: 0.857

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.826

GnomAD4 exome AF: 0.834 AC: 1218218 AN: 1461374 Hom.: 512317 Cov.: 66 AF XY: 0.830 AC XY: 603151 AN XY: 726988

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.800

Gnomad4 ASJ exome AF: 0.875

Gnomad4 EAS exome AF: 0.890

Gnomad4 SAS exome AF: 0.665

Gnomad4 FIN exome AF: 0.862

Gnomad4 NFE exome AF: 0.856

Gnomad4 OTH exome AF: 0.822

GnomAD4 genome AF: 0.738 AC: 112330 AN: 152190 Hom.: 43669 Cov.: 33 AF XY: 0.741 AC XY: 55175 AN XY: 74414

Gnomad4 AFR AF: 0.466

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.880

Gnomad4 EAS AF: 0.865

Gnomad4 SAS AF: 0.667

Gnomad4 FIN AF: 0.858

Gnomad4 NFE AF: 0.855

Gnomad4 OTH AF: 0.768

Alfa AF: 0.833 Hom.: 47863

Bravo AF: 0.727

Asia WGS AF: 0.773 AC: 2686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory and autonomic neuropathy with spastic paraplegia Benign:3

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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

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	-0.72
CADD	Benign	2.1
DANN	Benign	0.84

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: rs2548546; hg19: chr5-10250430; COSMIC: COSV54723145; COSMIC: COSV54723145;