21-46431839-A-G

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.8375A>G(p.Gln2792Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,546 control chromosomes in the GnomAD database, including 322,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34980 hom., cov: 34)

Exomes 𝑓: 0.63 ( 287790 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0810

Publications

52 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=6.886558E-7).

BP6

Variant 21-46431839-A-G is Benign according to our data. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in CliVar as Benign. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.8375A>G	p.Gln2792Arg	missense_variant	Exon 38 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.8021A>G	p.Gln2674Arg	missense_variant	Exon 38 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.8375A>G	p.Gln2792Arg	missense_variant	Exon 38 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.671

AC:

102083

AN:

152028

Hom.:

34935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.790

Gnomad AMI

AF:

0.727

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.743

Gnomad EAS

AF:

0.638

Gnomad SAS

AF:

0.625

Gnomad FIN

AF:

0.606

Gnomad MID

AF:

0.734

Gnomad NFE

AF:

0.631

Gnomad OTH

AF:

0.695

GnomAD2 exomes

AF:

0.627

AC:

156951

AN:

250436

AF XY:

0.629

show subpopulations

Gnomad AFR exome

AF:

0.794

Gnomad AMR exome

AF:

0.483

Gnomad ASJ exome

AF:

0.735

Gnomad EAS exome

AF:

0.633

Gnomad FIN exome

AF:

0.617

Gnomad NFE exome

AF:

0.639

Gnomad OTH exome

AF:

0.629

GnomAD4 exome

AF:

0.625

AC:

913994

AN:

1461402

Hom.:

287790

Cov.:

AF XY:

0.627

AC XY:

455793

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.804

AC:

26918

AN:

33480

American (AMR)

AF:

0.495

AC:

22144

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.735

AC:

19218

AN:

26134

East Asian (EAS)

AF:

0.674

AC:

26738

AN:

39700

South Asian (SAS)

AF:

0.621

AC:

53584

AN:

86244

European-Finnish (FIN)

AF:

0.617

AC:

32710

AN:

53056

Middle Eastern (MID)

AF:

0.730

AC:

4212

AN:

5766

European-Non Finnish (NFE)

AF:

0.620

AC:

689795

AN:

1111934

Other (OTH)

AF:

0.640

AC:

38675

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

24291

48583

72874

97166

121457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18488

36976

55464

73952

92440

<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:

0.672

AC:

102180

AN:

152144

Hom.:

34980

Cov.:

AF XY:

0.666

AC XY:

49559

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.791

AC:

32841

AN:

41538

American (AMR)

AF:

0.576

AC:

8806

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.743

AC:

2579

AN:

3470

East Asian (EAS)

AF:

0.639

AC:

3303

AN:

5170

South Asian (SAS)

AF:

0.626

AC:

3022

AN:

4828

European-Finnish (FIN)

AF:

0.606

AC:

6398

AN:

10552

Middle Eastern (MID)

AF:

0.721

AC:

212

AN:

294

European-Non Finnish (NFE)

AF:

0.631

AC:

42891

AN:

67984

Other (OTH)

AF:

0.696

AC:

1471

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1730

3459

5189

6918

8648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.644

Hom.:

117146

Bravo

AF:

0.675

TwinsUK

AF:

0.616

AC:

2284

ALSPAC

AF:

0.617

AC:

2376

ESP6500AA

AF:

0.792

AC:

3491

ESP6500EA

AF:

0.640

AC:

5507

ExAC

AF:

0.639

AC:

77537

Asia WGS

AF:

0.679

AC:

2360

AN:

3478

EpiCase

AF:

0.635

EpiControl

AF:

0.645

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCNT-related disorder

Benign:1

Jul 19, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.0

(source)

DANN

Benign

0.11

DEOGEN2

Benign

0.022

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.22

MetaRNN

Benign

6.9e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.9

PhyloP100

0.081

PrimateAI

Benign

0.28

PROVEAN

Benign

1.8

REVEL

Benign

0.031

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.031

MPC

0.087

ClinPred

0.0013

GERP RS

2.3

Varity_R

0.016

gMVP

0.023

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over