chr5-10250318-G-A

Variant names:

• chr5-10250318-G-A
• rs2548546
• NM_012073.5:c.-23G>A

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: -0.574
• Publications: 27 publications found

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]

CCT5 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy with spastic paraplegia

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
CCT5	NM_012073.5	c.-23G>A		5_prime_UTR_variant	Exon 1 of 11	ENST00000280326.9	NP_036205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCT5	ENST00000280326.9	c.-23G>A		5_prime_UTR_variant	Exon 1 of 11	1	NM_012073.5	ENSP00000280326.4

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

GnomAD2 exomes AF: 0.799 AC: 199959 AN: 250370 AF XY: 0.799

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 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

African (AFR) AF: 0.448 AC: 15006 AN: 33472

American (AMR) AF: 0.800 AC: 35755 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 22866 AN: 26132

East Asian (EAS) AF: 0.890 AC: 35326 AN: 39698

South Asian (SAS) AF: 0.665 AC: 57314 AN: 86220

European-Finnish (FIN) AF: 0.862 AC: 45780 AN: 53118

Middle Eastern (MID) AF: 0.788 AC: 4548 AN: 5768

European-Non Finnish (NFE) AF: 0.856 AC: 951976 AN: 1111908

Other (OTH) AF: 0.822 AC: 49647 AN: 60384

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

African (AFR) AF: 0.466 AC: 19346 AN: 41506

American (AMR) AF: 0.808 AC: 12358 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 3053 AN: 3470

East Asian (EAS) AF: 0.865 AC: 4472 AN: 5168

South Asian (SAS) AF: 0.667 AC: 3213 AN: 4820

European-Finnish (FIN) AF: 0.858 AC: 9107 AN: 10612

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.855 AC: 58155 AN: 68004

Other (OTH) AF: 0.768 AC: 1623 AN: 2114

Alfa AF: 0.817 Hom.: 59636

Bravo AF: 0.727

Asia WGS AF: 0.773 AC: 2686 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory and autonomic neuropathy with spastic paraplegia Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.1
DANN	Benign	0.84
PhyloP100		-0.57
PromoterAI		-0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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