rs113591604

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006031.6(PCNT):c.9707G>A(p.Arg3236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,720 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 9 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 0.00600

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047527254).

BP6

Variant 21-46443816-G-A is Benign according to our data. Variant chr21-46443816-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197527.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00238 (362/152296) while in subpopulation NFE AF = 0.00409 (278/68014). AF 95% confidence interval is 0.00369. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.9707G>A	p.Arg3236Gln	missense_variant	Exon 45 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.9116G>A	p.Arg3039Gln	missense_variant	Exon 45 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.9707G>A	p.Arg3236Gln	missense_variant	Exon 45 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

361

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00409

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00220

AC:

552

AN:

251138

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00378

AC:

5530

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00362

AC XY:

2630

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33464

American (AMR)

AF:

0.00208

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26134

East Asian (EAS)

AF:

0.000428

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00464

AC:

5165

AN:

1111970

Other (OTH)

AF:

0.00330

AC:

199

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

265

529

794

1058

1323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00238

AC:

362

AN:

152296

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

41552

American (AMR)

AF:

0.00189

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00409

AC:

278

AN:

68014

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00329

Hom.:

Bravo

AF:

0.00242

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00226

AC:

274

EpiCase

AF:

0.00442

EpiControl

AF:

0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Mar 27, 2018

GeneDx

Significance:Likely 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. -

Apr 22, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCNT: BP4 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jul 02, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 31, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCNT-related disorder

Benign:1

May 26, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Jan 29, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.2

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.030

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.46

M_CAP

Benign

0.015

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PhyloP100

0.0060

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.97

REVEL

Benign

0.062

Sift

Benign

0.58

Sift4G

Benign

0.29

Polyphen

0.84

Vest4

0.10

MVP

0.42

MPC

0.29

ClinPred

0.018

GERP RS

-0.84

Varity_R

0.026

gMVP

0.29

Mutation Taster

=97/3

polymorphism

(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