chr21-46367087-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.3113T>C(p.Val1038Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,613,630 control chromosomes in the GnomAD database, including 610,688 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 0.87 ( 57696 hom., cov: 32)

Exomes 𝑓: 0.87 ( 552992 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.194

Publications

46 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=9.449875E-7).

BP6

Variant 21-46367087-T-C is Benign according to our data. Variant chr21-46367087-T-C is described in ClinVar as Benign. ClinVar VariationId is 159581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.3113T>C	p.Val1038Ala	missense_variant	Exon 15 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.2759T>C	p.Val920Ala	missense_variant	Exon 15 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.3113T>C	p.Val1038Ala	missense_variant	Exon 15 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.870

AC:

132358

AN:

152088

Hom.:

57659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.899

Gnomad AMI

AF:

0.793

Gnomad AMR

AF:

0.838

Gnomad ASJ

AF:

0.876

Gnomad EAS

AF:

0.808

Gnomad SAS

AF:

0.789

Gnomad FIN

AF:

0.842

Gnomad MID

AF:

0.877

Gnomad NFE

AF:

0.876

Gnomad OTH

AF:

0.875

GnomAD2 exomes

AF:

0.853

AC:

212763

AN:

249528

AF XY:

0.850

show subpopulations

Gnomad AFR exome

AF:

0.900

Gnomad AMR exome

AF:

0.834

Gnomad ASJ exome

AF:

0.888

Gnomad EAS exome

AF:

0.816

Gnomad FIN exome

AF:

0.839

Gnomad NFE exome

AF:

0.875

Gnomad OTH exome

AF:

0.870

GnomAD4 exome

AF:

0.869

AC:

1270245

AN:

1461424

Hom.:

552992

Cov.:

AF XY:

0.866

AC XY:

629436

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.900

AC:

30128

AN:

33480

American (AMR)

AF:

0.833

AC:

37234

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

23241

AN:

26134

East Asian (EAS)

AF:

0.779

AC:

30914

AN:

39698

South Asian (SAS)

AF:

0.788

AC:

68001

AN:

86256

European-Finnish (FIN)

AF:

0.842

AC:

44603

AN:

52992

Middle Eastern (MID)

AF:

0.836

AC:

4820

AN:

5768

European-Non Finnish (NFE)

AF:

0.880

AC:

978885

AN:

1111980

Other (OTH)

AF:

0.868

AC:

52419

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

10287

20574

30860

41147

51434

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:

0.870

AC:

132453

AN:

152206

Hom.:

57696

Cov.:

AF XY:

0.864

AC XY:

64292

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.898

AC:

37338

AN:

41558

American (AMR)

AF:

0.838

AC:

12820

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.876

AC:

3038

AN:

3470

East Asian (EAS)

AF:

0.807

AC:

4158

AN:

5150

South Asian (SAS)

AF:

0.788

AC:

3803

AN:

4824

European-Finnish (FIN)

AF:

0.842

AC:

8922

AN:

10592

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.876

AC:

59544

AN:

68004

Other (OTH)

AF:

0.876

AC:

1850

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

890

1780

2671

3561

4451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.873

Hom.:

164481

Bravo

AF:

0.873

TwinsUK

AF:

0.877

AC:

3253

ALSPAC

AF:

0.883

AC:

3404

ESP6500AA

AF:

0.898

AC:

3958

ESP6500EA

AF:

0.875

AC:

7527

ExAC

AF:

0.852

AC:

103477

Asia WGS

AF:

0.800

AC:

2784

AN:

3478

EpiCase

AF:

0.873

EpiControl

AF:

0.874

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 12, 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. -

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

- -

not provided

Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Jun 22, 2016

Eurofins Ntd Llc (ga)

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

0.082

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0040

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.031

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.10

MetaRNN

Benign

9.4e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.34

PhyloP100

-0.19

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

REVEL

Benign

0.041

Sift

Benign

0.64

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.0050

MPC

0.097

ClinPred

0.025

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.047

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