21-46430570-G-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.7977G>C(p.Gln2659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,559,684 control chromosomes in the GnomAD database, including 228,653 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 19204 hom., cov: 33)

Exomes 𝑓: 0.54 ( 209449 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.90

Publications

47 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=2.4640954E-6).

BP6

Variant 21-46430570-G-C is Benign according to our data. Variant chr21-46430570-G-C is described in ClinVar as [Benign]. Clinvar id is 159670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.7977G>C	p.Gln2659His	missense_variant	Exon 37 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.7623G>C	p.Gln2541His	missense_variant	Exon 37 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.7977G>C	p.Gln2659His	missense_variant	Exon 37 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.491

AC:

74529

AN:

151918

Hom.:

19196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.698

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.533

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.533

GnomAD2 exomes

AF:

0.526

AC:

90059

AN:

171372

AF XY:

0.533

show subpopulations

Gnomad AFR exome

AF:

0.329

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.650

Gnomad EAS exome

AF:

0.622

Gnomad FIN exome

AF:

0.510

Gnomad NFE exome

AF:

0.558

Gnomad OTH exome

AF:

0.541

GnomAD4 exome

AF:

0.543

AC:

764307

AN:

1407648

Hom.:

209449

Cov.:

AF XY:

0.545

AC XY:

379032

AN XY:

695260

show subpopulations

African (AFR)

AF:

0.335

AC:

10771

AN:

32178

American (AMR)

AF:

0.440

AC:

16196

AN:

36826

Ashkenazi Jewish (ASJ)

AF:

0.651

AC:

16469

AN:

25286

East Asian (EAS)

AF:

0.673

AC:

24717

AN:

36732

South Asian (SAS)

AF:

0.535

AC:

42739

AN:

79884

European-Finnish (FIN)

AF:

0.512

AC:

25455

AN:

49728

Middle Eastern (MID)

AF:

0.646

AC:

2786

AN:

4316

European-Non Finnish (NFE)

AF:

0.547

AC:

593582

AN:

1084422

Other (OTH)

AF:

0.542

AC:

31592

AN:

58276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

22776

45552

68328

91104

113880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16852

33704

50556

67408

84260

<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:

0.491

AC:

74577

AN:

152036

Hom.:

19204

Cov.:

AF XY:

0.489

AC XY:

36296

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.344

AC:

14270

AN:

41514

American (AMR)

AF:

0.481

AC:

7348

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

2279

AN:

3470

East Asian (EAS)

AF:

0.632

AC:

3252

AN:

5142

South Asian (SAS)

AF:

0.534

AC:

2572

AN:

4818

European-Finnish (FIN)

AF:

0.499

AC:

5273

AN:

10570

Middle Eastern (MID)

AF:

0.622

AC:

183

AN:

294

European-Non Finnish (NFE)

AF:

0.554

AC:

37648

AN:

67936

Other (OTH)

AF:

0.530

AC:

1117

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1873

3746

5620

7493

9366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.524

Hom.:

6086

Bravo

AF:

0.484

TwinsUK

AF:

0.550

AC:

2041

ALSPAC

AF:

0.544

AC:

2097

ESP6500AA

AF:

0.342

AC:

1499

ESP6500EA

AF:

0.557

AC:

4764

ExAC

AF:

0.453

AC:

51092

Asia WGS

AF:

0.571

AC:

1985

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

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

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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

- -

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

- -

Nov 23, 2014

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

0.14

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0020

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.19

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0000025

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PhyloP100

-2.9

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

REVEL

Benign

0.083

Sift

Benign

0.093

Sift4G

Uncertain

0.032

Polyphen

0.031

Vest4

0.066

MutPred

0.16

Loss of stability (P = 0.1486);

MPC

0.34

ClinPred

0.021

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.078

Mutation Taster

=96/4

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