chr21-46432171-G-A

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.8707G>A(p.Ala2903Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0707 in 1,613,078 control chromosomes in the GnomAD database, including 4,377 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2903P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.056 ( 305 hom., cov: 34)

Exomes 𝑓: 0.072 ( 4072 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.30

Publications

19 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=0.0019298196).

BP6

Variant 21-46432171-G-A is Benign according to our data. Variant chr21-46432171-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.8707G>A	p.Ala2903Thr	missense_variant	Exon 38 of 47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 link	c.8160+193G>A		intron_variant	Intron 38 of 46		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.8707G>A	p.Ala2903Thr	missense_variant	Exon 38 of 47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8584

AN:

152250

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.0597

Gnomad ASJ

AF:

0.0835

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.0741

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0801

Gnomad OTH

AF:

0.0713

GnomAD2 exomes

AF:

0.0610

AC:

15089

AN:

247396

AF XY:

0.0619

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0340

Gnomad ASJ exome

AF:

0.0892

Gnomad EAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.0745

Gnomad NFE exome

AF:

0.0828

Gnomad OTH exome

AF:

0.0695

GnomAD4 exome

AF:

0.0722

AC:

105536

AN:

1460710

Hom.:

4072

Cov.:

AF XY:

0.0715

AC XY:

51964

AN XY:

726584

show subpopulations

African (AFR)

AF:

0.0132

AC:

441

AN:

33458

American (AMR)

AF:

0.0368

AC:

1646

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0867

AC:

2266

AN:

26134

East Asian (EAS)

AF:

0.0126

AC:

499

AN:

39692

South Asian (SAS)

AF:

0.0458

AC:

3947

AN:

86206

European-Finnish (FIN)

AF:

0.0760

AC:

4033

AN:

53054

Middle Eastern (MID)

AF:

0.0564

AC:

305

AN:

5412

European-Non Finnish (NFE)

AF:

0.0796

AC:

88550

AN:

1111754

Other (OTH)

AF:

0.0638

AC:

3849

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

6213

12427

18640

24854

31067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3132

6264

9396

12528

15660

<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:

0.0563

AC:

8582

AN:

152368

Hom.:

305

Cov.:

AF XY:

0.0560

AC XY:

4170

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0161

AC:

669

AN:

41600

American (AMR)

AF:

0.0596

AC:

912

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0835

AC:

290

AN:

3472

East Asian (EAS)

AF:

0.0100

AC:

AN:

5190

South Asian (SAS)

AF:

0.0418

AC:

202

AN:

4830

European-Finnish (FIN)

AF:

0.0741

AC:

787

AN:

10616

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0801

AC:

5448

AN:

68032

Other (OTH)

AF:

0.0710

AC:

150

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

431

862

1293

1724

2155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0745

Hom.:

1611

Bravo

AF:

0.0533

TwinsUK

AF:

0.0841

AC:

312

ALSPAC

AF:

0.0791

AC:

305

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0828

AC:

712

ExAC

AF:

0.0612

AC:

7432

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0819

EpiControl

AF:

0.0838

ClinVar

Significance: Benign/Likely 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

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCNT-related disorder

Benign:1

Feb 01, 2023

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). -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

Jan 12, 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

0.091

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.018

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.88

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

PhyloP100

5.3

PrimateAI

Benign

0.31

PROVEAN

Benign

0.070

REVEL

Benign

0.083

Sift

Benign

0.23

Sift4G

Benign

0.46

Polyphen

0.089

Vest4

0.056

MPC

0.36

ClinPred

0.017

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.058

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