5-10256049-T-C

Variant names:

• chr5-10256049-T-C
• rs1042392
• NM_012073.5:c.426T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012073.5(CCT5):​c.426T>C​(p.Arg142Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 1,613,930 control chromosomes in the GnomAD database, including 565,720 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. R142R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.75 (44475 hom., cov: 34)
  • Exomes 𝑓: 0.84 (521245 hom.)
• Consequence: CCT5 NM_012073.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0520
• Publications: 34 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 5-10256049-T-C is Benign according to our data. Variant chr5-10256049-T-C is described in ClinVar as Benign. ClinVar VariationId is 350249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCT5	NM_012073.5	MANE Select	c.426T>C	p.Arg142Arg	synonymous	Exon 4 of 11	NP_036205.1	P48643-1
	CCT5	NM_001306153.1		c.363T>C	p.Arg121Arg	synonymous	Exon 4 of 11	NP_001293082.1	B4DX08
	CCT5	NM_001306156.2		c.312T>C	p.Arg104Arg	synonymous	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.426T>C	p.Arg142Arg	synonymous	Exon 4 of 11	ENSP00000280326.4	P48643-1
	CCT5	ENST00000964556.1		c.426T>C	p.Arg142Arg	synonymous	Exon 4 of 11	ENSP00000634615.1
	CCT5	ENST00000964554.1		c.426T>C	p.Arg142Arg	synonymous	Exon 4 of 11	ENSP00000634613.1

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113508 AN: 152126 Hom.: 44459 Cov.: 34

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.803

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.774

GnomAD2 exomes AF: 0.804 AC: 202101 AN: 251312 AF XY: 0.804

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.865

Gnomad EAS exome AF: 0.872

Gnomad FIN exome AF: 0.858

Gnomad NFE exome AF: 0.862

Gnomad OTH exome AF: 0.829

GnomAD4 exome AF: 0.841 AC: 1228930 AN: 1461686 Hom.: 521245 Cov.: 46 AF XY: 0.837 AC XY: 608271 AN XY: 727144

African (AFR) AF: 0.461 AC: 15427 AN: 33472

American (AMR) AF: 0.803 AC: 35905 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 22811 AN: 26134

East Asian (EAS) AF: 0.894 AC: 35485 AN: 39698

South Asian (SAS) AF: 0.666 AC: 57408 AN: 86244

European-Finnish (FIN) AF: 0.863 AC: 46076 AN: 53404

Middle Eastern (MID) AF: 0.790 AC: 4555 AN: 5764

European-Non Finnish (NFE) AF: 0.865 AC: 961273 AN: 1111876

Other (OTH) AF: 0.828 AC: 49990 AN: 60382

GnomAD4 genome AF: 0.746 AC: 113565 AN: 152244 Hom.: 44475 Cov.: 34 AF XY: 0.749 AC XY: 55743 AN XY: 74430

African (AFR) AF: 0.480 AC: 19905 AN: 41498

American (AMR) AF: 0.813 AC: 12438 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3047 AN: 3470

East Asian (EAS) AF: 0.873 AC: 4530 AN: 5188

South Asian (SAS) AF: 0.666 AC: 3214 AN: 4828

European-Finnish (FIN) AF: 0.859 AC: 9109 AN: 10600

Middle Eastern (MID) AF: 0.812 AC: 237 AN: 292

European-Non Finnish (NFE) AF: 0.862 AC: 58678 AN: 68042

Other (OTH) AF: 0.775 AC: 1639 AN: 2114

Alfa AF: 0.813 Hom.: 26176

Bravo AF: 0.735

Asia WGS AF: 0.774 AC: 2691 AN: 3478

EpiCase AF: 0.861

EpiControl AF: 0.861

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary sensory and autonomic neuropathy with spastic paraplegia (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		0.052
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs1042392; hg19: chr5-10256161; COSMIC: COSV54723227; COSMIC: COSV54723227;