chr21-46416633-T-C

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.6715T>C(p.Trp2239Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,570,834 control chromosomes in the GnomAD database, including 12,147 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. W2239S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 4565 hom., cov: 32)

Exomes 𝑓: 0.082 ( 7582 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.142

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=1.8361211E-4).

BP6

Variant 21-46416633-T-C is Benign according to our data. Variant chr21-46416633-T-C is described in ClinVar as Benign. ClinVar VariationId is 138626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.6715T>C	p.Trp2239Arg	missense_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.6361T>C	p.Trp2121Arg	missense_variant	Exon 30 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.6715T>C	p.Trp2239Arg	missense_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27268

AN:

152018

Hom.:

4560

Cov.:

show subpopulations

Gnomad AFR

AF:

0.443

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0951

Gnomad ASJ

AF:

0.0866

Gnomad EAS

AF:

0.00560

Gnomad SAS

AF:

0.0936

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0765

Gnomad OTH

AF:

0.164

GnomAD2 exomes

AF:

0.0972

AC:

20538

AN:

211278

AF XY:

0.0913

show subpopulations

Gnomad AFR exome

AF:

0.452

Gnomad AMR exome

AF:

0.0543

Gnomad ASJ exome

AF:

0.0853

Gnomad EAS exome

AF:

0.00316

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.0742

Gnomad OTH exome

AF:

0.0838

GnomAD4 exome

AF:

0.0817

AC:

115889

AN:

1418698

Hom.:

7582

Cov.:

AF XY:

0.0808

AC XY:

56670

AN XY:

701322

show subpopulations

African (AFR)

AF:

0.464

AC:

14896

AN:

32122

American (AMR)

AF:

0.0589

AC:

2352

AN:

39928

Ashkenazi Jewish (ASJ)

AF:

0.0838

AC:

1913

AN:

22826

East Asian (EAS)

AF:

0.00170

AC:

AN:

39420

South Asian (SAS)

AF:

0.0843

AC:

6600

AN:

78314

European-Finnish (FIN)

AF:

0.103

AC:

5198

AN:

50334

Middle Eastern (MID)

AF:

0.0727

AC:

398

AN:

5478

European-Non Finnish (NFE)

AF:

0.0721

AC:

78741

AN:

1091856

Other (OTH)

AF:

0.0980

AC:

5724

AN:

58420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

5968

11935

17903

23870

29838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3102

6204

9306

12408

15510

<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:

0.179

AC:

27306

AN:

152136

Hom.:

4565

Cov.:

AF XY:

0.176

AC XY:

13119

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.442

AC:

18336

AN:

41466

American (AMR)

AF:

0.0948

AC:

1451

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0866

AC:

300

AN:

3466

East Asian (EAS)

AF:

0.00561

AC:

AN:

5170

South Asian (SAS)

AF:

0.0935

AC:

451

AN:

4826

European-Finnish (FIN)

AF:

0.107

AC:

1135

AN:

10616

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0764

AC:

5196

AN:

67974

Other (OTH)

AF:

0.168

AC:

355

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

962

1924

2885

3847

4809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.132

Hom.:

1181

Bravo

AF:

0.189

TwinsUK

AF:

0.0653

AC:

242

ALSPAC

AF:

0.0724

AC:

279

ESP6500AA

AF:

0.413

AC:

1811

ESP6500EA

AF:

0.0731

AC:

627

ExAC

AF:

0.100

AC:

12129

Asia WGS

AF:

0.106

AC:

367

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 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

0.069

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.7

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.013

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.040

MetaRNN

Benign

0.00018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-0.14

PrimateAI

Benign

0.21

PROVEAN

Benign

0.44

REVEL

Benign

0.021

Sift

Benign

0.36

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.037

MutPred

0.18

Loss of catalytic residue at W2239 (P = 0.0018);

MPC

0.15

ClinPred

0.0029

GERP RS

1.3

Varity_R

0.038

gMVP

0.21

Mutation Taster

=100/0

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