chr21-46334649-A-G

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.520A>G(p.Ile174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,568,000 control chromosomes in the GnomAD database, including 1,546 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 0.039 ( 128 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1418 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.64

Publications

10 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=0.0017138422).

BP6

Variant 21-46334649-A-G is Benign according to our data. Variant chr21-46334649-A-G is described in ClinVar as Benign. ClinVar VariationId is 138613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.520A>G	p.Ile174Val	missense_variant	Exon 3 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.166A>G	p.Ile56Val	missense_variant	Exon 3 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.520A>G	p.Ile174Val	missense_variant	Exon 3 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5356

AN:

138672

Hom.:

130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0282

Gnomad AMI

AF:

0.0652

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.000407

Gnomad SAS

AF:

0.0198

Gnomad FIN

AF:

0.00611

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0480

Gnomad OTH

AF:

0.0547

GnomAD2 exomes

AF:

0.0322

AC:

8016

AN:

248896

AF XY:

0.0330

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.0263

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00704

Gnomad NFE exome

AF:

0.0437

Gnomad OTH exome

AF:

0.0433

GnomAD4 exome

AF:

0.0352

AC:

50271

AN:

1429206

Hom.:

1418

Cov.:

AF XY:

0.0353

AC XY:

25108

AN XY:

711208

show subpopulations

African (AFR)

AF:

0.0205

AC:

668

AN:

32522

American (AMR)

AF:

0.0265

AC:

1151

AN:

43464

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2718

AN:

24428

East Asian (EAS)

AF:

0.000281

AC:

AN:

39176

South Asian (SAS)

AF:

0.0142

AC:

1197

AN:

84462

European-Finnish (FIN)

AF:

0.00816

AC:

430

AN:

52674

Middle Eastern (MID)

AF:

0.0781

AC:

441

AN:

5644

European-Non Finnish (NFE)

AF:

0.0380

AC:

41377

AN:

1088072

Other (OTH)

AF:

0.0388

AC:

2278

AN:

58764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3537

7074

10611

14148

17685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1472

2944

4416

5888

7360

<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:

0.0386

AC:

5354

AN:

138794

Hom.:

128

Cov.:

AF XY:

0.0360

AC XY:

2449

AN XY:

68016

show subpopulations

African (AFR)

AF:

0.0282

AC:

1019

AN:

36108

American (AMR)

AF:

0.0394

AC:

556

AN:

14116

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

398

AN:

3190

East Asian (EAS)

AF:

0.000408

AC:

AN:

4904

South Asian (SAS)

AF:

0.0201

AC:

AN:

4384

European-Finnish (FIN)

AF:

0.00611

AC:

AN:

9492

Middle Eastern (MID)

AF:

0.0977

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0480

AC:

3048

AN:

63536

Other (OTH)

AF:

0.0530

AC:

102

AN:

1924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

268

535

803

1070

1338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0457

Hom.:

TwinsUK

AF:

0.0448

AC:

166

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.0247

AC:

109

ESP6500EA

AF:

0.0557

AC:

479

ExAC

AF:

0.0328

AC:

3969

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 23, 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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0050

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.014

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00039

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

PhyloP100

-1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.18

REVEL

Benign

0.010

Sift

Benign

0.24

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.033

MPC

0.068

ClinPred

0.0043

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.023

Mutation Taster

=99/1

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