rs2073380

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006031.6(PCNT):c.9735A>C(p.Arg3245Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,004 control chromosomes in the GnomAD database, including 40,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3087 hom., cov: 32)

Exomes 𝑓: 0.22 ( 36950 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0960

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011502206).

BP6

Variant 21-46443844-A-C is Benign according to our data. Variant chr21-46443844-A-C is described in ClinVar as [Benign]. Clinvar id is 159697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46443844-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.9735A>C	p.Arg3245Ser	missense_variant	45/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.9144A>C	p.Arg3048Ser	missense_variant	45/47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.9735A>C	p.Arg3245Ser	missense_variant	45/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28256

AN:

152032

Hom.:

3089

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0800

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.218

Gnomad OTH

AF:

0.205

GnomAD3 exomes

AF:

0.225

AC:

56476

AN:

251232

Hom.:

7071

AF XY:

0.229

AC XY:

31169

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0756

Gnomad AMR exome

AF:

0.165

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.434

Gnomad SAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.224

Gnomad OTH exome

AF:

0.232

GnomAD4 exome

AF:

0.219

AC:

319941

AN:

1460854

Hom.:

36950

Cov.:

AF XY:

0.221

AC XY:

160506

AN XY:

726764

show subpopulations

Gnomad4 AFR exome

AF:

0.0750

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.232

Gnomad4 EAS exome

AF:

0.445

Gnomad4 SAS exome

AF:

0.233

Gnomad4 FIN exome

AF:

0.246

Gnomad4 NFE exome

AF:

0.214

Gnomad4 OTH exome

AF:

0.226

GnomAD4 genome

AF:

0.186

AC:

28257

AN:

152150

Hom.:

3087

Cov.:

AF XY:

0.186

AC XY:

13867

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0800

Gnomad4 AMR

AF:

0.166

Gnomad4 ASJ

AF:

0.236

Gnomad4 EAS

AF:

0.428

Gnomad4 SAS

AF:

0.242

Gnomad4 FIN

AF:

0.241

Gnomad4 NFE

AF:

0.218

Gnomad4 OTH

AF:

0.205

Alfa

AF:

0.209

Hom.:

3407

Bravo

AF:

0.178

TwinsUK

AF:

0.212

AC:

785

ALSPAC

AF:

0.218

AC:

842

ESP6500AA

AF:

0.0808

AC:

356

ESP6500EA

AF:

0.215

AC:

1849

ExAC

AF:

0.228

AC:

27660

Asia WGS

AF:

0.302

AC:

1049

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.8

DANN

Benign

0.40

DEOGEN2

Benign

0.013

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0012

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.48

PROVEAN

Benign

0.41

REVEL

Benign

0.013

Sift

Benign

0.73

Sift4G

Benign

0.70

Polyphen

0.010

Vest4

0.039

MutPred

0.32

Gain of phosphorylation at R3245 (P = 0.0025);

MPC

0.29

ClinPred

0.0098

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over