rs141675330

chr5-10261652-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012073.5(CCT5):c.1086C>G(p.Ile362Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,614,074 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (41 hom.)
• Consequence: CCT5 NM_012073.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.96

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 (MetaRNN=0.009223521).
• BP6: Variant 5-10261652-C-G is Benign according to our data. Variant chr5-10261652-C-G is described in ClinVar as [Benign]. Clinvar id is 240839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-10261652-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00612 (8942/1461812) while in subpopulation AMR AF= 0.017 (759/44722). AF 95% confidence interval is 0.016. There are 41 homozygotes in gnomad4_exome. There are 4291 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCT5	NM_012073.5	c.1086C>G	p.Ile362Met	missense_variant	8/11	ENST00000280326.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCT5	ENST00000280326.9	c.1086C>G	p.Ile362Met	missense_variant	8/11	1	NM_012073.5	P1

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 726 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00689

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00603 AC: 1517 AN: 251478 Hom.: 11 AF XY: 0.00567 AC XY: 770 AN XY: 135910

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.00564

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00612 AC: 8942 AN: 1461812 Hom.: 41 Cov.: 32 AF XY: 0.00590 AC XY: 4291 AN XY: 727210

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00822

Gnomad4 NFE exome AF: 0.00645

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.00477 AC: 726 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00490 AC XY: 365 AN XY: 74458

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00689

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00550 Hom.: 1

Bravo AF: 0.00511

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00541 AC: 657

EpiCase AF: 0.00578

EpiControl AF: 0.00492

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CCT5: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.5	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.51	N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.10	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.0060	B;.;B;.;.
Vest4		0.32
MVP		0.47
MPC		0.39
ClinPred		0.014	T
GERP RS		3.6
Varity_R		0.25
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs141675330; hg19: chr5-10261764; COSMIC: COSV99039966; COSMIC: COSV99039966;