rs699113

Variant names:

• chr5-10264964-C-T
• rs699113
• NM_012073.5:c.*181C>T

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.*181C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 681,050 control chromosomes in the GnomAD database, including 224,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (43703 hom., cov: 33)
  • Exomes 𝑓: 0.82 (181217 hom.)
• Consequence: CCT5 NM_012073.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.68
• Publications: 19 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

ENSG00000271980 (HGNC:58210):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-10264964-C-T is Benign according to our data. Variant chr5-10264964-C-T is described in ClinVar as Benign. ClinVar VariationId is 350264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012073.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	NM_012073.5	MANE Select	c.*181C>T		3_prime_UTR	Exon 11 of 11	NP_036205.1
	CCT5	NM_001306153.1		c.*181C>T		3_prime_UTR	Exon 11 of 11	NP_001293082.1
	CCT5	NM_001306156.2		c.*181C>T		3_prime_UTR	Exon 11 of 11	NP_001293085.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	ENST00000280326.9	TSL:1 MANE Select	c.*181C>T		3_prime_UTR	Exon 11 of 11	ENSP00000280326.4
	ENSG00000271980	ENST00000606194.1	TSL:6	n.2183G>A		non_coding_transcript_exon	Exon 1 of 1
	CCT5	ENST00000503026.5	TSL:2	c.*181C>T		3_prime_UTR	Exon 11 of 11	ENSP00000423318.1

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112319 AN: 152018 Hom.: 43686 Cov.: 33

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.877

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.856

Gnomad OTH AF: 0.767

GnomAD4 exome AF: 0.823 AC: 435437 AN: 528914 Hom.: 181217 Cov.: 7 AF XY: 0.817 AC XY: 226924 AN XY: 277792

African (AFR) AF: 0.462 AC: 6437 AN: 13942

American (AMR) AF: 0.797 AC: 15043 AN: 18882

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 12211 AN: 13964

East Asian (EAS) AF: 0.894 AC: 27417 AN: 30684

South Asian (SAS) AF: 0.662 AC: 31688 AN: 47902

European-Finnish (FIN) AF: 0.862 AC: 28299 AN: 32830

Middle Eastern (MID) AF: 0.776 AC: 1632 AN: 2104

European-Non Finnish (NFE) AF: 0.851 AC: 289591 AN: 340344

Other (OTH) AF: 0.818 AC: 23119 AN: 28262

GnomAD4 genome AF: 0.739 AC: 112376 AN: 152136 Hom.: 43703 Cov.: 33 AF XY: 0.742 AC XY: 55199 AN XY: 74386

African (AFR) AF: 0.466 AC: 19327 AN: 41430

American (AMR) AF: 0.809 AC: 12378 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.877 AC: 3039 AN: 3466

East Asian (EAS) AF: 0.866 AC: 4489 AN: 5184

South Asian (SAS) AF: 0.664 AC: 3209 AN: 4832

European-Finnish (FIN) AF: 0.859 AC: 9102 AN: 10592

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.856 AC: 58207 AN: 68020

Other (OTH) AF: 0.768 AC: 1624 AN: 2114

Alfa AF: 0.809 Hom.: 32773

Bravo AF: 0.727

Asia WGS AF: 0.773 AC: 2686 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

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

Hereditary sensory and autonomic neuropathy with spastic paraplegia Benign:1

Jan 12, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.89
DANN	Benign	0.81
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs699113; hg19: chr5-10265076;