chr21-46416739-C-T

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.6821C>T(p.Pro2274Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,595,446 control chromosomes in the GnomAD database, including 63,931 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2274P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.25 ( 5061 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58870 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0470

Publications

28 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=0.005088061).

BP6

Variant 21-46416739-C-T is Benign according to our data. Variant chr21-46416739-C-T is described in ClinVar as Benign. ClinVar VariationId is 159642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.6821C>T	p.Pro2274Leu	missense_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.6467C>T	p.Pro2156Leu	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.6821C>T	p.Pro2274Leu	missense_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37879

AN:

151998

Hom.:

5063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.388

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.274

GnomAD2 exomes

AF:

0.270

AC:

63152

AN:

234236

AF XY:

0.274

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.388

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.284

GnomAD4 exome

AF:

0.283

AC:

408344

AN:

1443328

Hom.:

58870

Cov.:

AF XY:

0.283

AC XY:

202782

AN XY:

715744

show subpopulations

African (AFR)

AF:

0.175

AC:

5817

AN:

33220

American (AMR)

AF:

0.200

AC:

8747

AN:

43756

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

7348

AN:

25048

East Asian (EAS)

AF:

0.396

AC:

15616

AN:

39448

South Asian (SAS)

AF:

0.261

AC:

22055

AN:

84618

European-Finnish (FIN)

AF:

0.243

AC:

12275

AN:

50570

Middle Eastern (MID)

AF:

0.350

AC:

1930

AN:

5522

European-Non Finnish (NFE)

AF:

0.288

AC:

317622

AN:

1101630

Other (OTH)

AF:

0.285

AC:

16934

AN:

59516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16717

33434

50150

66867

83584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10670

21340

32010

42680

53350

<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:

0.249

AC:

37883

AN:

152118

Hom.:

5061

Cov.:

AF XY:

0.245

AC XY:

18201

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.175

AC:

7269

AN:

41524

American (AMR)

AF:

0.215

AC:

3289

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

1013

AN:

3470

East Asian (EAS)

AF:

0.389

AC:

2003

AN:

5154

South Asian (SAS)

AF:

0.268

AC:

1295

AN:

4826

European-Finnish (FIN)

AF:

0.236

AC:

2495

AN:

10588

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.287

AC:

19532

AN:

67960

Other (OTH)

AF:

0.273

AC:

576

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1458

2916

4373

5831

7289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.277

Hom.:

5042

Bravo

AF:

0.246

TwinsUK

AF:

0.292

AC:

1084

ALSPAC

AF:

0.296

AC:

1142

ESP6500AA

AF:

0.164

AC:

653

ESP6500EA

AF:

0.256

AC:

2011

ExAC

AF:

0.269

AC:

31834

Asia WGS

AF:

0.306

AC:

1066

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:3

May 31, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.1

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.014

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.047

PrimateAI

Benign

0.25

PROVEAN

Benign

0.030

REVEL

Benign

0.0060

Sift

Benign

0.65

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.018

MPC

0.082

ClinPred

0.00030

GERP RS

-0.65

Varity_R

0.027

gMVP

0.18

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