21-46416481-T-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.6563T>G(p.Met2188Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,613,944 control chromosomes in the GnomAD database, including 12,116 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 0.18 ( 4412 hom., cov: 32)

Exomes 𝑓: 0.082 ( 7704 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.160

Publications

19 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=3.4615397E-4).

BP6

Variant 21-46416481-T-G is Benign according to our data. Variant chr21-46416481-T-G is described in ClinVar as Benign. ClinVar VariationId is 138624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 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.6563T>G	p.Met2188Arg	missense	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6209T>G	p.Met2070Arg	missense	Exon 30 of 47	NP_001302458.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCNT	ENST00000359568.10	TSL:1 MANE Select	c.6563T>G	p.Met2188Arg	missense	Exon 30 of 47	ENSP00000352572.5
PCNT	ENST00000480896.5	TSL:1	c.6209T>G	p.Met2070Arg	missense	Exon 30 of 47	ENSP00000511989.1
PCNT	ENST00000695558.1		c.6596T>G	p.Met2199Arg	missense	Exon 31 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26946

AN:

152094

Hom.:

4407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.435

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0943

Gnomad ASJ

AF:

0.0865

Gnomad EAS

AF:

0.00560

Gnomad SAS

AF:

0.0923

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0763

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.0958

AC:

24089

AN:

251338

AF XY:

0.0906

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.0552

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.0749

Gnomad OTH exome

AF:

0.0823

GnomAD4 exome

AF:

0.0818

AC:

119506

AN:

1461732

Hom.:

7704

Cov.:

AF XY:

0.0809

AC XY:

58823

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.456

AC:

15253

AN:

33478

American (AMR)

AF:

0.0597

AC:

2671

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

2217

AN:

26136

East Asian (EAS)

AF:

0.00169

AC:

AN:

39700

South Asian (SAS)

AF:

0.0848

AC:

7314

AN:

86254

European-Finnish (FIN)

AF:

0.104

AC:

5551

AN:

53330

Middle Eastern (MID)

AF:

0.0735

AC:

424

AN:

5768

European-Non Finnish (NFE)

AF:

0.0721

AC:

80126

AN:

1111950

Other (OTH)

AF:

0.0974

AC:

5883

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

6625

13250

19874

26499

33124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3096

6192

9288

12384

15480

<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:

0.177

AC:

26984

AN:

152212

Hom.:

4412

Cov.:

AF XY:

0.174

AC XY:

12951

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.434

AC:

18035

AN:

41514

American (AMR)

AF:

0.0941

AC:

1439

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0865

AC:

300

AN:

3470

East Asian (EAS)

AF:

0.00561

AC:

AN:

5170

South Asian (SAS)

AF:

0.0922

AC:

445

AN:

4826

European-Finnish (FIN)

AF:

0.108

AC:

1144

AN:

10606

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0763

AC:

5188

AN:

68008

Other (OTH)

AF:

0.166

AC:

351

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

976

1952

2929

3905

4881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<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:

0.119

Hom.:

4159

Bravo

AF:

0.187

TwinsUK

AF:

0.0650

AC:

241

ALSPAC

AF:

0.0724

AC:

279

ESP6500AA

AF:

0.434

AC:

1911

ESP6500EA

AF:

0.0758

AC:

652

ExAC

AF:

0.104

AC:

12590

Asia WGS

AF:

0.104

AC:

362

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0707

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 26, 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

not provided

Benign:2

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.4

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.015

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0086

LIST_S2

Benign

0.13

MetaRNN

Benign

0.00035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

PhyloP100

0.16

PrimateAI

Benign

0.19

PROVEAN

Benign

0.75

REVEL

Benign

0.029

Sift

Benign

0.33

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.036

MPC

0.12

ClinPred

0.0051

GERP RS

-0.74

Varity_R

0.12

gMVP

0.20

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

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