rs6518291

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.4915A>G(p.Ile1639Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,280 control chromosomes in the GnomAD database, including 44,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 8761 hom., cov: 31)

Exomes 𝑓: 0.21 ( 36046 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.63

Publications

41 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=4.7264406E-5).

BP6

Variant 21-46401674-A-G is Benign according to our data. Variant chr21-46401674-A-G is described in ClinVar as Benign. ClinVar VariationId is 159613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.4915A>G	p.Ile1639Val	missense_variant	Exon 26 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.4561A>G	p.Ile1521Val	missense_variant	Exon 26 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.4915A>G	p.Ile1639Val	missense_variant	Exon 26 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46355

AN:

151522

Hom.:

8742

Cov.:

show subpopulations

Gnomad AFR

AF:

0.536

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.197

Gnomad SAS

AF:

0.302

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.282

GnomAD2 exomes

AF:

0.242

AC:

60698

AN:

251320

AF XY:

0.239

show subpopulations

Gnomad AFR exome

AF:

0.543

Gnomad AMR exome

AF:

0.215

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.269

Gnomad NFE exome

AF:

0.199

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.212

AC:

309294

AN:

1461640

Hom.:

36046

Cov.:

AF XY:

0.214

AC XY:

155690

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.555

AC:

18590

AN:

33476

American (AMR)

AF:

0.222

AC:

9941

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5088

AN:

26130

East Asian (EAS)

AF:

0.219

AC:

8679

AN:

39700

South Asian (SAS)

AF:

0.296

AC:

25565

AN:

86254

European-Finnish (FIN)

AF:

0.261

AC:

13949

AN:

53392

Middle Eastern (MID)

AF:

0.238

AC:

1374

AN:

5768

European-Non Finnish (NFE)

AF:

0.191

AC:

212304

AN:

1111802

Other (OTH)

AF:

0.229

AC:

13804

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12937

25873

38810

51746

64683

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7548

15096

22644

30192

37740

<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:

0.306

AC:

46423

AN:

151640

Hom.:

8761

Cov.:

AF XY:

0.309

AC XY:

22923

AN XY:

74084

show subpopulations

African (AFR)

AF:

0.536

AC:

22138

AN:

41288

American (AMR)

AF:

0.253

AC:

3859

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

728

AN:

3466

East Asian (EAS)

AF:

0.198

AC:

1020

AN:

5160

South Asian (SAS)

AF:

0.303

AC:

1447

AN:

4780

European-Finnish (FIN)

AF:

0.266

AC:

2792

AN:

10498

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13560

AN:

67914

Other (OTH)

AF:

0.287

AC:

602

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1470

2940

4410

5880

7350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.234

Hom.:

15125

Bravo

AF:

0.312

TwinsUK

AF:

0.187

AC:

693

ALSPAC

AF:

0.188

AC:

723

ESP6500AA

AF:

0.536

AC:

2361

ESP6500EA

AF:

0.200

AC:

1718

ExAC

AF:

0.249

AC:

30243

Asia WGS

AF:

0.309

AC:

1071

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.195

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

0.067

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.18

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.014

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00049

LIST_S2

Benign

0.093

MetaRNN

Benign

0.000047

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.81

PhyloP100

1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

0.50

REVEL

Benign

0.18

Sift

Benign

0.35

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.0090

MPC

0.068

ClinPred

0.011

GERP RS

1.8

Varity_R

0.015

gMVP

0.020

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