rs35044802

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.3580G>A(p.Ala1194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,608,322 control chromosomes in the GnomAD database, including 1,611 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. A1194V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 132 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1479 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.630

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001982838).

BP6

Variant 21-46388857-G-A is Benign according to our data. Variant chr21-46388857-G-A is described in ClinVar as Benign. ClinVar VariationId is 159590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.3580G>A	p.Ala1194Thr	missense_variant	Exon 18 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.3226G>A	p.Ala1076Thr	missense_variant	Exon 18 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.3580G>A	p.Ala1194Thr	missense_variant	Exon 18 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5277

AN:

152174

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0445

Gnomad OTH

AF:

0.0498

GnomAD2 exomes

AF:

0.0360

AC:

8749

AN:

243052

AF XY:

0.0364

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.0279

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.00802

Gnomad NFE exome

AF:

0.0486

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0403

AC:

58616

AN:

1456030

Hom.:

1479

Cov.:

AF XY:

0.0403

AC XY:

29160

AN XY:

724472

show subpopulations

African (AFR)

AF:

0.0233

AC:

777

AN:

33418

American (AMR)

AF:

0.0301

AC:

1342

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3113

AN:

26092

East Asian (EAS)

AF:

0.000101

AC:

AN:

39686

South Asian (SAS)

AF:

0.0183

AC:

1578

AN:

86086

European-Finnish (FIN)

AF:

0.00892

AC:

444

AN:

49762

Middle Eastern (MID)

AF:

0.0841

AC:

396

AN:

4708

European-Non Finnish (NFE)

AF:

0.0435

AC:

48368

AN:

1111540

Other (OTH)

AF:

0.0431

AC:

2594

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3581

7161

10742

14322

17903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1740

3480

5220

6960

8700

<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:

0.0346

AC:

5276

AN:

152292

Hom.:

132

Cov.:

AF XY:

0.0325

AC XY:

2417

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0232

AC:

966

AN:

41570

American (AMR)

AF:

0.0359

AC:

549

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

402

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0180

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00546

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0445

AC:

3030

AN:

68018

Other (OTH)

AF:

0.0483

AC:

102

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

256

512

768

1024

1280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0464

Hom.:

527

Bravo

AF:

0.0379

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.0544

AC:

468

ExAC

AF:

0.0349

AC:

4229

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

- -

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:2

Aug 22, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.98

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.018

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

PhyloP100

-0.63

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.020

REVEL

Benign

0.055

Sift

Benign

0.72

Sift4G

Benign

0.20

Polyphen

0.34

Vest4

0.019

MPC

0.078

ClinPred

0.0041

GERP RS

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.051

Mutation Taster

=97/3

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