rs2839245

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.6290T>C(p.Leu2097Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,614,020 control chromosomes in the GnomAD database, including 12,097 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L2097L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 4397 hom., cov: 32)

Exomes 𝑓: 0.082 ( 7700 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.677

Publications

30 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=2.3597479E-4).

BP6

Variant 21-46416208-T-C is Benign according to our data. Variant chr21-46416208-T-C is described in ClinVar as Benign. ClinVar VariationId is 138621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.6290T>C	p.Leu2097Pro	missense_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.5936T>C	p.Leu1979Pro	missense_variant	Exon 30 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.6290T>C	p.Leu2097Pro	missense_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26876

AN:

152062

Hom.:

4392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0944

Gnomad ASJ

AF:

0.0864

Gnomad EAS

AF:

0.00558

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0762

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.0958

AC:

24089

AN:

251432

AF XY:

0.0904

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.0551

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.0748

Gnomad OTH exome

AF:

0.0823

GnomAD4 exome

AF:

0.0817

AC:

119448

AN:

1461840

Hom.:

7700

Cov.:

AF XY:

0.0808

AC XY:

58794

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.456

AC:

15257

AN:

33474

American (AMR)

AF:

0.0596

AC:

2667

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0849

AC:

2218

AN:

26136

East Asian (EAS)

AF:

0.00169

AC:

AN:

39700

South Asian (SAS)

AF:

0.0849

AC:

7320

AN:

86256

European-Finnish (FIN)

AF:

0.103

AC:

5525

AN:

53414

Middle Eastern (MID)

AF:

0.0735

AC:

424

AN:

5768

European-Non Finnish (NFE)

AF:

0.0720

AC:

80091

AN:

1111978

Other (OTH)

AF:

0.0973

AC:

5879

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

6697

13394

20090

26787

33484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3098

6196

9294

12392

15490

<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:

0.177

AC:

26914

AN:

152180

Hom.:

4397

Cov.:

AF XY:

0.174

AC XY:

12916

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.434

AC:

17977

AN:

41446

American (AMR)

AF:

0.0942

AC:

1441

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0864

AC:

300

AN:

3472

East Asian (EAS)

AF:

0.00559

AC:

AN:

5188

South Asian (SAS)

AF:

0.0920

AC:

444

AN:

4826

European-Finnish (FIN)

AF:

0.107

AC:

1136

AN:

10620

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0762

AC:

5182

AN:

68010

Other (OTH)

AF:

0.167

AC:

352

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

936

1871

2807

3742

4678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<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:

0.106

Hom.:

5553

Bravo

AF:

0.187

TwinsUK

AF:

0.0653

AC:

242

ALSPAC

AF:

0.0724

AC:

279

ESP6500AA

AF:

0.434

AC:

1913

ESP6500EA

AF:

0.0758

AC:

652

ExAC

AF:

0.104

AC:

12576

Asia WGS

AF:

0.104

AC:

362

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0706

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 26, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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

- -

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

0.053

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.020

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.16

MetaRNN

Benign

0.00024

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.1

PhyloP100

-0.68

PrimateAI

Benign

0.21

PROVEAN

Benign

0.53

REVEL

Benign

0.024

Sift

Benign

0.34

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.019

MPC

0.13

ClinPred

0.00077

GERP RS

-1.5

Varity_R

0.049

gMVP

0.074

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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