chr21-46422027-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.7082A>G(p.Gln2361Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,746 control chromosomes in the GnomAD database, including 12,117 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 ( 4409 hom., cov: 33)

Exomes 𝑓: 0.082 ( 7708 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.239

Publications

24 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=2.9194355E-4).

BP6

Variant 21-46422027-A-G is Benign according to our data. Variant chr21-46422027-A-G is described in ClinVar as Benign. ClinVar VariationId is 138630.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.7082A>G	p.Gln2361Arg	missense	Exon 32 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6728A>G	p.Gln2243Arg	missense	Exon 32 of 47	NP_001302458.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCNT	ENST00000359568.10	TSL:1 MANE Select	c.7082A>G	p.Gln2361Arg	missense	Exon 32 of 47	ENSP00000352572.5
PCNT	ENST00000480896.5	TSL:1	c.6728A>G	p.Gln2243Arg	missense	Exon 32 of 47	ENSP00000511989.1
PCNT	ENST00000695558.1		c.7115A>G	p.Gln2372Arg	missense	Exon 33 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26897

AN:

152002

Hom.:

4402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.435

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.0942

Gnomad ASJ

AF:

0.0863

Gnomad EAS

AF:

0.00562

Gnomad SAS

AF:

0.0918

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0762

Gnomad OTH

AF:

0.163

GnomAD2 exomes

AF:

0.0958

AC:

24047

AN:

251132

AF XY:

0.0905

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:

0.108

Gnomad NFE exome

AF:

0.0746

Gnomad OTH exome

AF:

0.0823

GnomAD4 exome

AF:

0.0817

AC:

119443

AN:

1461626

Hom.:

7708

Cov.:

AF XY:

0.0809

AC XY:

58799

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.456

AC:

15275

AN:

33474

American (AMR)

AF:

0.0597

AC:

2671

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

2217

AN:

26134

East Asian (EAS)

AF:

0.00169

AC:

AN:

39700

South Asian (SAS)

AF:

0.0850

AC:

7330

AN:

86258

European-Finnish (FIN)

AF:

0.103

AC:

5505

AN:

53296

Middle Eastern (MID)

AF:

0.0735

AC:

424

AN:

5768

European-Non Finnish (NFE)

AF:

0.0720

AC:

80058

AN:

1111892

Other (OTH)

AF:

0.0976

AC:

5896

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

5800

11600

17401

23201

29001

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:

26938

AN:

152120

Hom.:

4409

Cov.:

AF XY:

0.174

AC XY:

12935

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.434

AC:

18014

AN:

41464

American (AMR)

AF:

0.0939

AC:

1437

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0863

AC:

299

AN:

3466

East Asian (EAS)

AF:

0.00563

AC:

AN:

5150

South Asian (SAS)

AF:

0.0917

AC:

443

AN:

4830

European-Finnish (FIN)

AF:

0.107

AC:

1131

AN:

10590

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0762

AC:

5181

AN:

68004

Other (OTH)

AF:

0.166

AC:

351

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

913

1825

2738

3650

4563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.0908

Hom.:

2174

Bravo

AF:

0.187

TwinsUK

AF:

0.0626

AC:

232

ALSPAC

AF:

0.0688

AC:

265

ESP6500AA

AF:

0.434

AC:

1914

ESP6500EA

AF:

0.0758

AC:

652

ExAC

AF:

0.103

AC:

12569

Asia WGS

AF:

0.105

AC:

366

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0706

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.30

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.053

Eigen

Benign

-2.0

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.12

MetaRNN

Benign

0.00029

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.24

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.71

REVEL

Benign

0.027

Sift

Benign

0.34

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.062

MPC

0.087

ClinPred

0.0058

GERP RS

1.3

Varity_R

0.020

gMVP

0.16

Mutation Taster

=98/2

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over