rs34151633

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.6571T>C(p.Ser2191Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,614,058 control chromosomes in the GnomAD database, including 1,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2191Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 147 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1597 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0120

Publications

12 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=0.0026471317).

BP6

Variant 21-46416489-T-C is Benign according to our data. Variant chr21-46416489-T-C is described in ClinVar as [Benign]. Clinvar id is 159634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.6571T>C	p.Ser2191Pro	missense_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.6217T>C	p.Ser2073Pro	missense_variant	Exon 30 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.6571T>C	p.Ser2191Pro	missense_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5164

AN:

152216

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.0637

Gnomad AMR

AF:

0.0370

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0451

Gnomad OTH

AF:

0.0497

GnomAD2 exomes

AF:

0.0369

AC:

9263

AN:

251262

AF XY:

0.0373

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.0285

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00744

Gnomad NFE exome

AF:

0.0493

Gnomad OTH exome

AF:

0.0510

GnomAD4 exome

AF:

0.0412

AC:

60161

AN:

1461724

Hom.:

1597

Cov.:

AF XY:

0.0412

AC XY:

29941

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0166

AC:

557

AN:

33480

American (AMR)

AF:

0.0310

AC:

1385

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

3856

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0184

AC:

1586

AN:

86258

European-Finnish (FIN)

AF:

0.00873

AC:

465

AN:

53278

Middle Eastern (MID)

AF:

0.0829

AC:

478

AN:

5768

European-Non Finnish (NFE)

AF:

0.0442

AC:

49100

AN:

1111988

Other (OTH)

AF:

0.0452

AC:

2730

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

3541

7082

10624

14165

17706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0339

AC:

5162

AN:

152334

Hom.:

147

Cov.:

AF XY:

0.0315

AC XY:

2346

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0166

AC:

692

AN:

41584

American (AMR)

AF:

0.0370

AC:

566

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

503

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0182

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00546

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0451

AC:

3070

AN:

68026

Other (OTH)

AF:

0.0482

AC:

102

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

269

539

808

1078

1347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0481

Hom.:

1355

Bravo

AF:

0.0373

TwinsUK

AF:

0.0413

AC:

153

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.0560

AC:

482

ExAC

AF:

0.0360

AC:

4367

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0589

EpiControl

AF:

0.0580

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.054

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.7

PhyloP100

0.012

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

REVEL

Benign

0.025

Sift

Benign

0.25

Sift4G

Benign

0.15

Polyphen

0.98

Vest4

0.097

MPC

0.34

ClinPred

0.0035

GERP RS

0.73

Varity_R

0.13

gMVP

0.15

Mutation Taster

=95/5

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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rs34151633

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