21-46363881-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006031.6(PCNT):c.2556T>C(p.Ala852Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 1,612,428 control chromosomes in the GnomAD database, including 611,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 58784 hom., cov: 33)

Exomes 𝑓: 0.87 ( 552706 hom. )

Consequence

PCNT
NM_006031.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.303

Publications

23 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 21-46363881-T-C is Benign according to our data. Variant chr21-46363881-T-C is described in ClinVar as Benign. ClinVar VariationId is 159572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.303 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.2556T>C	p.Ala852Ala	synonymous	Exon 14 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.2202T>C	p.Ala734Ala	synonymous	Exon 14 of 47	NP_001302458.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCNT	ENST00000359568.10	TSL:1 MANE Select	c.2556T>C	p.Ala852Ala	synonymous	Exon 14 of 47	ENSP00000352572.5
PCNT	ENST00000480896.5	TSL:1	c.2202T>C	p.Ala734Ala	synonymous	Exon 14 of 47	ENSP00000511989.1
PCNT	ENST00000695558.1		c.2556T>C	p.Ala852Ala	synonymous	Exon 14 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes

AF:

0.878

AC:

133554

AN:

152132

Hom.:

58738

Cov.:

show subpopulations

Gnomad AFR

AF:

0.927

Gnomad AMI

AF:

0.793

Gnomad AMR

AF:

0.841

Gnomad ASJ

AF:

0.875

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.788

Gnomad FIN

AF:

0.841

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.875

Gnomad OTH

AF:

0.881

GnomAD2 exomes

AF:

0.854

AC:

210903

AN:

246928

AF XY:

0.851

show subpopulations

Gnomad AFR exome

AF:

0.927

Gnomad AMR exome

AF:

0.835

Gnomad ASJ exome

AF:

0.888

Gnomad EAS exome

AF:

0.817

Gnomad FIN exome

AF:

0.839

Gnomad NFE exome

AF:

0.874

Gnomad OTH exome

AF:

0.870

GnomAD4 exome

AF:

0.869

AC:

1269348

AN:

1460178

Hom.:

552706

Cov.:

AF XY:

0.866

AC XY:

628910

AN XY:

726394

show subpopulations

African (AFR)

AF:

0.926

AC:

31003

AN:

33468

American (AMR)

AF:

0.834

AC:

37277

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

23206

AN:

26100

East Asian (EAS)

AF:

0.779

AC:

30938

AN:

39694

South Asian (SAS)

AF:

0.789

AC:

67995

AN:

86204

European-Finnish (FIN)

AF:

0.842

AC:

43905

AN:

52170

Middle Eastern (MID)

AF:

0.838

AC:

4798

AN:

5726

European-Non Finnish (NFE)

AF:

0.879

AC:

977741

AN:

1111774

Other (OTH)

AF:

0.870

AC:

52485

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

9890

19781

29671

39562

49452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21346

42692

64038

85384

106730

<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:

0.878

AC:

133659

AN:

152250

Hom.:

58784

Cov.:

AF XY:

0.872

AC XY:

64914

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.927

AC:

38518

AN:

41568

American (AMR)

AF:

0.841

AC:

12873

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.875

AC:

3039

AN:

3472

East Asian (EAS)

AF:

0.806

AC:

4158

AN:

5158

South Asian (SAS)

AF:

0.788

AC:

3803

AN:

4826

European-Finnish (FIN)

AF:

0.841

AC:

8926

AN:

10610

Middle Eastern (MID)

AF:

0.881

AC:

259

AN:

294

European-Non Finnish (NFE)

AF:

0.875

AC:

59499

AN:

68002

Other (OTH)

AF:

0.882

AC:

1861

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

850

1701

2551

3402

4252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.874

Hom.:

12141

Bravo

AF:

0.882

Asia WGS

AF:

0.803

AC:

2795

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 05, 2021

Genome-Nilou Lab

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.

Jun 28, 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

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

PCNT-related disorder

Benign:1

Jan 24, 2024

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).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.4

(source)

DANN

Benign

0.17

PhyloP100

0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over