Genetic Variant CCT5:p.Ala246Ala (chr5-10258400-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012073.5(CCT5):c.738G>A(p.Ala246Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,614,096 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A246A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 33)

Exomes 𝑓: 0.033 ( 927 hom. )

Consequence

CCT5
NM_012073.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.23

Publications

6 publications found

Variant links:

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

CCT5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 5-10258400-G-A is Benign according to our data. Variant chr5-10258400-G-A is described in ClinVar as Benign. ClinVar VariationId is 240841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0275 (4187/152276) while in subpopulation NFE AF = 0.0399 (2716/68032). AF 95% confidence interval is 0.0387. There are 73 homozygotes in GnomAd4. There are 2080 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 73 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCT5	NM_012073.5	MANE Select	c.738G>A	p.Ala246Ala	synonymous	Exon 6 of 11	NP_036205.1
CCT5	NM_001306153.1		c.675G>A	p.Ala225Ala	synonymous	Exon 6 of 11	NP_001293082.1
CCT5	NM_001306156.2		c.624G>A	p.Ala208Ala	synonymous	Exon 6 of 11	NP_001293085.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CCT5	ENST00000280326.9	TSL:1 MANE Select	c.738G>A	p.Ala246Ala	synonymous	Exon 6 of 11	ENSP00000280326.4
CCT5	ENST00000964556.1		c.738G>A	p.Ala246Ala	synonymous	Exon 6 of 11	ENSP00000634615.1
CCT5	ENST00000964554.1		c.762G>A	p.Ala254Ala	synonymous	Exon 6 of 11	ENSP00000634613.1

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4186

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.00307

Gnomad SAS

AF:

0.00995

Gnomad FIN

AF:

0.0592

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0399

Gnomad OTH

AF:

0.0248

GnomAD2 exomes

AF:

0.0273

AC:

6866

AN:

251472

AF XY:

0.0276

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0156

Gnomad ASJ exome

AF:

0.0397

Gnomad EAS exome

AF:

0.00391

Gnomad FIN exome

AF:

0.0541

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0306

GnomAD4 exome

AF:

0.0329

AC:

48047

AN:

1461820

Hom.:

927

Cov.:

AF XY:

0.0325

AC XY:

23660

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00430

AC:

144

AN:

33480

American (AMR)

AF:

0.0161

AC:

721

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0382

AC:

998

AN:

26136

East Asian (EAS)

AF:

0.00169

AC:

AN:

39700

South Asian (SAS)

AF:

0.0126

AC:

1091

AN:

86256

European-Finnish (FIN)

AF:

0.0555

AC:

2967

AN:

53418

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0362

AC:

40202

AN:

1111942

Other (OTH)

AF:

0.0301

AC:

1815

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2785

5569

8354

11138

13923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1426

2852

4278

5704

7130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0275

AC:

4187

AN:

152276

Hom.:

Cov.:

AF XY:

0.0279

AC XY:

2080

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00578

AC:

240

AN:

41546

American (AMR)

AF:

0.0201

AC:

307

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.00308

AC:

AN:

5194

South Asian (SAS)

AF:

0.0102

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0592

AC:

627

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0399

AC:

2716

AN:

68032

Other (OTH)

AF:

0.0246

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

222

444

666

888

1110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0303

Hom.:

Bravo

AF:

0.0229

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0327

EpiControl

AF:

0.0333

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary sensory and autonomic neuropathy with spastic paraplegia (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

3.6

(source)

DANN

Benign

0.55

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over