NM_012073.5:c.437A>T

Variant names:

• chr5-10256060-A-T
• rs11557652
• NM_012073.5:c.437A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012073.5(CCT5):​c.437A>T​(p.Glu146Val) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,614,140 control chromosomes in the GnomAD database, including 469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 33)
  • Exomes 𝑓: 0.022 (437 hom.)
• Consequence: CCT5 NM_012073.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.96
• Publications: 20 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 (MetaRNN=0.006799668).
• BP6: Variant 5-10256060-A-T is Benign according to our data. Variant chr5-10256060-A-T is described in ClinVar as Benign. ClinVar VariationId is 240840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.017 (2585/152354) while in subpopulation SAS AF = 0.049 (237/4832). AF 95% confidence interval is 0.0439. There are 32 homozygotes in GnomAd4. There are 1336 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR,AD,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	NM_012073.5	MANE Select	c.437A>T	p.Glu146Val	missense	Exon 4 of 11	NP_036205.1	P48643-1
	CCT5	NM_001306153.1		c.374A>T	p.Glu125Val	missense	Exon 4 of 11	NP_001293082.1	B4DX08
	CCT5	NM_001306156.2		c.323A>T	p.Glu108Val	missense	Exon 4 of 11	NP_001293085.1	B7ZAR1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	ENST00000280326.9	TSL:1 MANE Select	c.437A>T	p.Glu146Val	missense	Exon 4 of 11	ENSP00000280326.4	P48643-1
	CCT5	ENST00000964556.1		c.437A>T	p.Glu146Val	missense	Exon 4 of 11	ENSP00000634615.1
	CCT5	ENST00000964554.1		c.437A>T	p.Glu146Val	missense	Exon 4 of 11	ENSP00000634613.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2588 AN: 152236 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.00711

Gnomad SAS AF: 0.0498

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0228 AC: 5741 AN: 251378 AF XY: 0.0248

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.00892

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0224 AC: 32735 AN: 1461786 Hom.: 437 Cov.: 35 AF XY: 0.0233 AC XY: 16926 AN XY: 727190

African (AFR) AF: 0.00296 AC: 99 AN: 33474

American (AMR) AF: 0.0146 AC: 652 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 1057 AN: 26132

East Asian (EAS) AF: 0.00912 AC: 362 AN: 39700

South Asian (SAS) AF: 0.0467 AC: 4028 AN: 86250

European-Finnish (FIN) AF: 0.0269 AC: 1437 AN: 53410

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5766

European-Non Finnish (NFE) AF: 0.0212 AC: 23605 AN: 1111946

Other (OTH) AF: 0.0228 AC: 1376 AN: 60388

GnomAD4 genome AF: 0.0170 AC: 2585 AN: 152354 Hom.: 32 Cov.: 33 AF XY: 0.0179 AC XY: 1336 AN XY: 74502

African (AFR) AF: 0.00373 AC: 155 AN: 41572

American (AMR) AF: 0.0139 AC: 213 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3464

East Asian (EAS) AF: 0.00713 AC: 37 AN: 5190

South Asian (SAS) AF: 0.0490 AC: 237 AN: 4832

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1421 AN: 68042

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.0169 Hom.: 10

Bravo AF: 0.0139

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0224 AC: 193

ExAC AF: 0.0239 AC: 2903

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.0206

EpiControl AF: 0.0213

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary sensory and autonomic neuropathy with spastic paraplegia (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.010	D
Polyphen		0.26	B
Vest4		0.25
MPC		0.49
ClinPred		0.031	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.59
gMVP		0.64
Mutation Taster		=62/38	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: rs11557652; hg19: chr5-10256172;