NM_006031.6:c.9271A>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.9271A>G(p.Ser3091Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0256 in 1,613,794 control chromosomes in the GnomAD database, including 770 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3091R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 90 hom., cov: 33)

Exomes 𝑓: 0.026 ( 680 hom. )

Consequence

PCNT
NM_006031.6 missense, splice_region

Scores

Splicing: ADA: 0.2499

Clinical Significance

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

Conservation

PhyloP100: 3.79

Publications

20 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=0.0025025606).

BP6

Variant 21-46438335-A-G is Benign according to our data. Variant chr21-46438335-A-G is described in ClinVar as Benign. ClinVar VariationId is 138614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.9271A>G	p.Ser3091Gly	missense_variant, splice_region_variant	Exon 41 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.8680A>G	p.Ser2894Gly	missense_variant, splice_region_variant	Exon 41 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.9271A>G	p.Ser3091Gly	missense_variant, splice_region_variant	Exon 41 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3841

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0750

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.0434

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0336

AC:

8447

AN:

251206

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0997

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.00283

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0262

Gnomad OTH exome

AF:

0.0298

GnomAD4 exome

AF:

0.0256

AC:

37476

AN:

1461482

Hom.:

680

Cov.:

AF XY:

0.0255

AC XY:

18564

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.00394

AC:

132

AN:

33470

American (AMR)

AF:

0.0991

AC:

4430

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

358

AN:

26132

East Asian (EAS)

AF:

0.00582

AC:

231

AN:

39700

South Asian (SAS)

AF:

0.0210

AC:

1810

AN:

86240

European-Finnish (FIN)

AF:

0.0408

AC:

2177

AN:

53406

Middle Eastern (MID)

AF:

0.00910

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0242

AC:

26935

AN:

1111722

Other (OTH)

AF:

0.0224

AC:

1351

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1830

3661

5491

7322

9152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1012

2024

3036

4048

5060

<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:

0.0252

AC:

3843

AN:

152312

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

2002

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00483

AC:

201

AN:

41582

American (AMR)

AF:

0.0752

AC:

1151

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00309

AC:

AN:

5170

South Asian (SAS)

AF:

0.0178

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0434

AC:

461

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1758

AN:

68026

Other (OTH)

AF:

0.0279

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

186

371

557

742

928

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0246

Hom.:

190

Bravo

AF:

0.0267

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0235

AC:

202

ExAC

AF:

0.0307

AC:

3726

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 18, 2013

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.045

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

PhyloP100

3.8

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

REVEL

Benign

0.069

Sift

Benign

0.20

Sift4G

Benign

0.072

Polyphen

0.82

Vest4

0.037

MPC

0.21

ClinPred

0.028

GERP RS

5.0

Varity_R

0.062

gMVP

0.028

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.25

dbscSNV1_RF

Benign

0.23

SpliceAI score (max)

0.15

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