rs35940413

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.5522A>G(p.Asn1841Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,612,692 control chromosomes in the GnomAD database, including 19,522 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1841N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.21 ( 5452 hom., cov: 33)

Exomes 𝑓: 0.12 ( 14070 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.395

Publications

17 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=2.9724836E-4).

BP6

Variant 21-46411595-A-G is Benign according to our data. Variant chr21-46411595-A-G is described in ClinVar as Benign. ClinVar VariationId is 95336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.5522A>G	p.Asn1841Ser	missense_variant	Exon 28 of 47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 link	c.5168A>G	p.Asn1723Ser	missense_variant	Exon 28 of 47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.5522A>G	p.Asn1841Ser	missense_variant	Exon 28 of 47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes

AF:

0.214

AC:

32584

AN:

151970

Hom.:

5447

Cov.:

show subpopulations

Gnomad AFR

AF:

0.464

Gnomad AMI

AF:

0.0910

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.00582

Gnomad SAS

AF:

0.111

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.213

GnomAD2 exomes

AF:

0.133

AC:

32782

AN:

247286

AF XY:

0.128

show subpopulations

Gnomad AFR exome

AF:

0.474

Gnomad AMR exome

AF:

0.0832

Gnomad ASJ exome

AF:

0.227

Gnomad EAS exome

AF:

0.00311

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.123

AC:

179693

AN:

1460598

Hom.:

14070

Cov.:

AF XY:

0.122

AC XY:

88755

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.485

AC:

16227

AN:

33462

American (AMR)

AF:

0.0904

AC:

4041

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

6069

AN:

26118

East Asian (EAS)

AF:

0.00189

AC:

AN:

39686

South Asian (SAS)

AF:

0.104

AC:

8964

AN:

86256

European-Finnish (FIN)

AF:

0.112

AC:

5881

AN:

52456

Middle Eastern (MID)

AF:

0.157

AC:

906

AN:

5768

European-Non Finnish (NFE)

AF:

0.116

AC:

128902

AN:

1111768

Other (OTH)

AF:

0.143

AC:

8628

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

9506

19011

28517

38022

47528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4730

9460

14190

18920

23650

<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:

0.214

AC:

32621

AN:

152094

Hom.:

5452

Cov.:

AF XY:

0.209

AC XY:

15550

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.463

AC:

19232

AN:

41494

American (AMR)

AF:

0.132

AC:

2015

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

802

AN:

3470

East Asian (EAS)

AF:

0.00583

AC:

AN:

5148

South Asian (SAS)

AF:

0.111

AC:

534

AN:

4806

European-Finnish (FIN)

AF:

0.112

AC:

1191

AN:

10606

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8230

AN:

67966

Other (OTH)

AF:

0.215

AC:

452

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1164

2328

3492

4656

5820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.147

Hom.:

2374

Bravo

AF:

0.227

TwinsUK

AF:

0.106

AC:

394

ALSPAC

AF:

0.105

AC:

404

ESP6500AA

AF:

0.458

AC:

2018

ESP6500EA

AF:

0.130

AC:

1114

ExAC

AF:

0.139

AC:

16895

Asia WGS

AF:

0.114

AC:

396

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.129

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

- -

Aug 07, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2013

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. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

PCNT-related disorder

Benign:1

Jul 19, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

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

0.074

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.41

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.015

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.26

MetaRNN

Benign

0.00030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.0

PhyloP100

0.40

PrimateAI

Benign

0.35

PROVEAN

Benign

0.62

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.016

MPC

0.065

ClinPred

0.0043

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.074

Mutation Taster

=96/4

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