21-46353263-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006031.6(PCNT):c.1616C>T(p.Thr539Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,838 control chromosomes in the GnomAD database, including 14,670 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1357 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13313 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.244

Publications

40 publications found

Variant links:

Genes affected

PCNT (HGNC:16068): (pericentrin) The protein encoded by this gene binds to calmodulin and is expressed in the centrosome. It is an integral component of the pericentriolar material (PCM). The protein contains a series of coiled-coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The protein interacts with the microtubule nucleation component gamma-tubulin and is likely important to normal functioning of the centrosomes, cytoskeleton, and cell-cycle progression. Mutations in this gene cause Seckel syndrome-4 and microcephalic osteodysplastic primordial dwarfism type II. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PCNT Gene-Disease associations (from GenCC):

microcephalic osteodysplastic primordial dwarfism type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Moyamoya disease
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

PCNT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0035569966).

BP6

Variant 21-46353263-C-T is Benign according to our data. Variant chr21-46353263-C-T is described in CliVar as Benign. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46353263-C-T is described in CliVar as Benign. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46353263-C-T is described in CliVar as Benign. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46353263-C-T is described in CliVar as Benign. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46353263-C-T is described in CliVar as Benign. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46353263-C-T is described in CliVar as Benign. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.1616C>T	p.Thr539Ile	missense_variant	Exon 10 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.1262C>T	p.Thr421Ile	missense_variant	Exon 10 of 47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.1616C>T	p.Thr539Ile	missense_variant	Exon 10 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19766

AN:

152074

Hom.:

1355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.147

AC:

36930

AN:

251422

AF XY:

0.150

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.130

AC:

190656

AN:

1461646

Hom.:

13313

Cov.:

AF XY:

0.134

AC XY:

97237

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.102

AC:

3404

AN:

33474

American (AMR)

AF:

0.167

AC:

7473

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2902

AN:

26134

East Asian (EAS)

AF:

0.216

AC:

8558

AN:

39700

South Asian (SAS)

AF:

0.209

AC:

18018

AN:

86246

European-Finnish (FIN)

AF:

0.158

AC:

8454

AN:

53384

Middle Eastern (MID)

AF:

0.162

AC:

937

AN:

5768

European-Non Finnish (NFE)

AF:

0.120

AC:

132952

AN:

1111838

Other (OTH)

AF:

0.132

AC:

7958

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

10338

20676

31015

41353

51691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4868

9736

14604

19472

24340

<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:

0.130

AC:

19788

AN:

152192

Hom.:

1357

Cov.:

AF XY:

0.136

AC XY:

10136

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.103

AC:

4284

AN:

41532

American (AMR)

AF:

0.161

AC:

2462

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

435

AN:

3472

East Asian (EAS)

AF:

0.192

AC:

993

AN:

5176

South Asian (SAS)

AF:

0.209

AC:

1007

AN:

4824

European-Finnish (FIN)

AF:

0.159

AC:

1681

AN:

10592

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.124

AC:

8445

AN:

67998

Other (OTH)

AF:

0.122

AC:

258

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

891

1781

2672

3562

4453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<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:

0.126

Hom.:

4759

Bravo

AF:

0.127

TwinsUK

AF:

0.122

AC:

452

ALSPAC

AF:

0.118

AC:

453

ESP6500AA

AF:

0.104

AC:

460

ESP6500EA

AF:

0.124

AC:

1070

ExAC

AF:

0.147

AC:

17838

Asia WGS

AF:

0.199

AC:

688

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.125

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

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

- -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

Jan 13, 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.4

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.11

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

0.24

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.015

Sift

Benign

0.11

Sift4G

Benign

0.38

Polyphen

0.14

Vest4

0.027

MPC

0.14

ClinPred

0.0066

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.044

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over