rs2839227

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.2635A>G(p.Thr879Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,858 control chromosomes in the GnomAD database, including 29,428 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T879T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 7074 hom., cov: 33)

Exomes 𝑓: 0.16 ( 22354 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.77

Publications

54 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=7.278025E-4).

BP6

Variant 21-46366609-A-G is Benign according to our data. Variant chr21-46366609-A-G is described in ClinVar as Benign. ClinVar VariationId is 159575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.2635A>G	p.Thr879Ala	missense_variant	Exon 15 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.2281A>G	p.Thr761Ala	missense_variant	Exon 15 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.2635A>G	p.Thr879Ala	missense_variant	Exon 15 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39424

AN:

152004

Hom.:

7049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.197

AC:

49393

AN:

250338

AF XY:

0.196

show subpopulations

Gnomad AFR exome

AF:

0.518

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.187

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.158

AC:

230292

AN:

1461736

Hom.:

22354

Cov.:

AF XY:

0.161

AC XY:

117162

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.532

AC:

17820

AN:

33478

American (AMR)

AF:

0.204

AC:

9101

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3277

AN:

26136

East Asian (EAS)

AF:

0.223

AC:

8865

AN:

39700

South Asian (SAS)

AF:

0.282

AC:

24360

AN:

86256

European-Finnish (FIN)

AF:

0.178

AC:

9518

AN:

53350

Middle Eastern (MID)

AF:

0.208

AC:

1197

AN:

5768

European-Non Finnish (NFE)

AF:

0.131

AC:

145340

AN:

1111932

Other (OTH)

AF:

0.179

AC:

10814

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

11429

22858

34286

45715

57144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5462

10924

16386

21848

27310

<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:

0.260

AC:

39503

AN:

152122

Hom.:

7074

Cov.:

AF XY:

0.263

AC XY:

19564

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.510

AC:

21171

AN:

41476

American (AMR)

AF:

0.223

AC:

3417

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

488

AN:

3472

East Asian (EAS)

AF:

0.199

AC:

1023

AN:

5146

South Asian (SAS)

AF:

0.294

AC:

1413

AN:

4808

European-Finnish (FIN)

AF:

0.181

AC:

1919

AN:

10604

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.137

AC:

9322

AN:

68006

Other (OTH)

AF:

0.240

AC:

507

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

1354

2708

4063

5417

6771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.176

Hom.:

12176

Bravo

AF:

0.270

TwinsUK

AF:

0.132

AC:

491

ALSPAC

AF:

0.129

AC:

497

ESP6500AA

AF:

0.501

AC:

2199

ESP6500EA

AF:

0.136

AC:

1168

ExAC

AF:

0.204

AC:

24797

Asia WGS

AF:

0.296

AC:

1027

AN:

3478

EpiCase

AF:

0.141

EpiControl

AF:

0.141

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 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 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

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.097

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.37

MetaRNN

Benign

0.00073

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

2.8

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.0

REVEL

Benign

0.047

Sift

Benign

0.31

Sift4G

Benign

0.56

Polyphen

0.17

Vest4

0.10

MPC

0.28

ClinPred

0.012

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.046

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