rs34500739

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.711T>G(p.His237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 1,612,714 control chromosomes in the GnomAD database, including 2,673 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H237R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.050 ( 231 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2442 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.738

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=0.0030015707).

BP6

Variant 21-46346199-T-G is Benign according to our data. Variant chr21-46346199-T-G is described in ClinVar as Benign. ClinVar VariationId is 138615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.711T>G	p.His237Gln	missense_variant	Exon 4 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.357T>G	p.His119Gln	missense_variant	Exon 4 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.711T>G	p.His237Gln	missense_variant	Exon 4 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0503

AC:

7631

AN:

151752

Hom.:

232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0339

Gnomad ASJ

AF:

0.0642

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.0846

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.0627

Gnomad OTH

AF:

0.0482

GnomAD2 exomes

AF:

0.0459

AC:

11544

AN:

251320

AF XY:

0.0452

show subpopulations

Gnomad AFR exome

AF:

0.0376

Gnomad AMR exome

AF:

0.0217

Gnomad ASJ exome

AF:

0.0648

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0861

Gnomad NFE exome

AF:

0.0611

Gnomad OTH exome

AF:

0.0499

GnomAD4 exome

AF:

0.0546

AC:

79811

AN:

1460848

Hom.:

2442

Cov.:

AF XY:

0.0535

AC XY:

38885

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.0356

AC:

1190

AN:

33458

American (AMR)

AF:

0.0235

AC:

1051

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

1664

AN:

26102

East Asian (EAS)

AF:

0.000101

AC:

AN:

39632

South Asian (SAS)

AF:

0.0135

AC:

1162

AN:

86246

European-Finnish (FIN)

AF:

0.0832

AC:

4433

AN:

53278

Middle Eastern (MID)

AF:

0.0298

AC:

172

AN:

5768

European-Non Finnish (NFE)

AF:

0.0603

AC:

67061

AN:

1111330

Other (OTH)

AF:

0.0509

AC:

3074

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3663

7326

10989

14652

18315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2430

4860

7290

9720

12150

<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:

0.0503

AC:

7634

AN:

151866

Hom.:

231

Cov.:

AF XY:

0.0496

AC XY:

3684

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.0380

AC:

1572

AN:

41400

American (AMR)

AF:

0.0338

AC:

515

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0642

AC:

222

AN:

3460

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00893

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0846

AC:

888

AN:

10498

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0627

AC:

4258

AN:

67946

Other (OTH)

AF:

0.0477

AC:

101

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

359

719

1078

1438

1797

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0543

Hom.:

607

Bravo

AF:

0.0457

TwinsUK

AF:

0.0539

AC:

200

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.0436

AC:

192

ESP6500EA

AF:

0.0614

AC:

528

ExAC

AF:

0.0465

AC:

5644

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0548

EpiControl

AF:

0.0541

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.061

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.7

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.013

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00020

LIST_S2

Benign

0.18

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.6

PhyloP100

0.74

PrimateAI

Benign

0.36

PROVEAN

Benign

0.78

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.050

MutPred

0.28

Loss of catalytic residue at L236 (P = 0.1265);

MPC

0.081

ClinPred

0.00022

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.038

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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