chr21-46428545-G-A

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.7645G>A(p.Ala2549Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 1,607,914 control chromosomes in the GnomAD database, including 11,990 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 (★★).

Frequency

Genomes: 𝑓 0.18 ( 4372 hom., cov: 34)

Exomes 𝑓: 0.081 ( 7618 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.596

Publications

21 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=4.3970346E-4).

BP6

Variant 21-46428545-G-A is Benign according to our data. Variant chr21-46428545-G-A is described in ClinVar as Benign. ClinVar VariationId is 138604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.7645G>A	p.Ala2549Thr	missense_variant	Exon 35 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.7291G>A	p.Ala2431Thr	missense_variant	Exon 35 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.7645G>A	p.Ala2549Thr	missense_variant	Exon 35 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26841

AN:

152186

Hom.:

4365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.433

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0932

Gnomad ASJ

AF:

0.0865

Gnomad EAS

AF:

0.00577

Gnomad SAS

AF:

0.0902

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0761

Gnomad OTH

AF:

0.162

GnomAD2 exomes

AF:

0.0954

AC:

22605

AN:

237018

AF XY:

0.0903

show subpopulations

Gnomad AFR exome

AF:

0.453

Gnomad AMR exome

AF:

0.0546

Gnomad ASJ exome

AF:

0.0869

Gnomad EAS exome

AF:

0.00314

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0756

Gnomad OTH exome

AF:

0.0823

GnomAD4 exome

AF:

0.0815

AC:

118564

AN:

1455610

Hom.:

7618

Cov.:

AF XY:

0.0806

AC XY:

58363

AN XY:

724206

show subpopulations

African (AFR)

AF:

0.454

AC:

15183

AN:

33432

American (AMR)

AF:

0.0589

AC:

2621

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.0849

AC:

2214

AN:

26072

East Asian (EAS)

AF:

0.00169

AC:

AN:

39646

South Asian (SAS)

AF:

0.0841

AC:

7230

AN:

86012

European-Finnish (FIN)

AF:

0.104

AC:

5133

AN:

49382

Middle Eastern (MID)

AF:

0.0753

AC:

388

AN:

5154

European-Non Finnish (NFE)

AF:

0.0719

AC:

79901

AN:

1111278

Other (OTH)

AF:

0.0969

AC:

5827

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6306

12612

18917

25223

31529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3086

6172

9258

12344

15430

<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:

0.177

AC:

26885

AN:

152304

Hom.:

4372

Cov.:

AF XY:

0.173

AC XY:

12904

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.433

AC:

17984

AN:

41550

American (AMR)

AF:

0.0929

AC:

1422

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0865

AC:

300

AN:

3470

East Asian (EAS)

AF:

0.00579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0900

AC:

435

AN:

4832

European-Finnish (FIN)

AF:

0.107

AC:

1135

AN:

10622

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0761

AC:

5176

AN:

68022

Other (OTH)

AF:

0.166

AC:

350

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

951

1902

2852

3803

4754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<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:

0.0869

Hom.:

1827

Bravo

AF:

0.186

TwinsUK

AF:

0.0653

AC:

242

ALSPAC

AF:

0.0721

AC:

278

ESP6500AA

AF:

0.428

AC:

1879

ESP6500EA

AF:

0.0762

AC:

654

ExAC

AF:

0.102

AC:

12233

Asia WGS

AF:

0.104

AC:

361

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 26, 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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

0.083

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.7

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.014

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.63

MetaRNN

Benign

0.00044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.53

PhyloP100

0.60

PrimateAI

Benign

0.35

PROVEAN

Benign

0.16

REVEL

Benign

0.027

Sift

Benign

0.88

Sift4G

Benign

0.55

Polyphen

0.46

Vest4

0.042

MPC

0.36

ClinPred

0.0085

GERP RS

0.66

Varity_R

0.030

gMVP

0.023

Mutation Taster

=99/1

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