chr21-46388764-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.3487C>T(p.Arg1163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,632 control chromosomes in the GnomAD database, including 15,306 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1285 hom., cov: 33)

Exomes 𝑓: 0.13 ( 14021 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.242

Publications

33 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=0.005921036).

BP6

Variant 21-46388764-C-T is Benign according to our data. Variant chr21-46388764-C-T is described in ClinVar as Benign. ClinVar VariationId is 159589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.3487C>T	p.Arg1163Cys	missense_variant	Exon 18 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.3133C>T	p.Arg1045Cys	missense_variant	Exon 18 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.3487C>T	p.Arg1163Cys	missense_variant	Exon 18 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18698

AN:

152082

Hom.:

1284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0690

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.148

AC:

37018

AN:

250838

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.0672

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.189

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.134

AC:

195571

AN:

1461432

Hom.:

14021

Cov.:

AF XY:

0.137

AC XY:

99781

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.0685

AC:

2293

AN:

33476

American (AMR)

AF:

0.163

AC:

7281

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2891

AN:

26130

East Asian (EAS)

AF:

0.222

AC:

8821

AN:

39694

South Asian (SAS)

AF:

0.214

AC:

18481

AN:

86246

European-Finnish (FIN)

AF:

0.160

AC:

8498

AN:

53190

Middle Eastern (MID)

AF:

0.166

AC:

947

AN:

5718

European-Non Finnish (NFE)

AF:

0.124

AC:

138300

AN:

1111886

Other (OTH)

AF:

0.133

AC:

8059

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

9725

19450

29174

38899

48624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5018

10036

15054

20072

25090

<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:

0.123

AC:

18718

AN:

152200

Hom.:

1285

Cov.:

AF XY:

0.129

AC XY:

9564

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0692

AC:

2874

AN:

41528

American (AMR)

AF:

0.158

AC:

2413

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

433

AN:

3466

East Asian (EAS)

AF:

0.201

AC:

1039

AN:

5172

South Asian (SAS)

AF:

0.212

AC:

1024

AN:

4822

European-Finnish (FIN)

AF:

0.161

AC:

1705

AN:

10606

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8750

AN:

67994

Other (OTH)

AF:

0.121

AC:

256

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

886

1772

2659

3545

4431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.127

Hom.:

2940

Bravo

AF:

0.118

TwinsUK

AF:

0.128

AC:

475

ALSPAC

AF:

0.121

AC:

466

ESP6500AA

AF:

0.0654

AC:

288

ESP6500EA

AF:

0.129

AC:

1110

ExAC

AF:

0.147

AC:

17865

Asia WGS

AF:

0.205

AC:

711

AN:

3478

EpiCase

AF:

0.130

EpiControl

AF:

0.130

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 14, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2016

Eurofins Ntd Llc (ga)

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

0.15

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.24

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.099

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.18

MPC

0.46

ClinPred

0.063

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.16

gMVP

0.11

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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