rs2070425

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.6821C>T(p.Pro2274Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,595,446 control chromosomes in the GnomAD database, including 63,931 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2274P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.25 ( 5061 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58870 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0470

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=0.005088061).

BP6

Variant 21-46416739-C-T is Benign according to our data. Variant chr21-46416739-C-T is described in ClinVar as [Benign]. Clinvar id is 159642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416739-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.6821C>T	p.Pro2274Leu	missense_variant	30/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 linkuse as main transcript	c.6467C>T	p.Pro2156Leu	missense_variant	30/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.6821C>T	p.Pro2274Leu	missense_variant	30/47	1	NM_006031.6	ENSP00000352572	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37879

AN:

151998

Hom.:

5063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.388

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.274

GnomAD3 exomes

AF:

0.270

AC:

63152

AN:

234236

Hom.:

8953

AF XY:

0.274

AC XY:

35048

AN XY:

128136

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.388

Gnomad SAS exome

AF:

0.256

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.284

GnomAD4 exome

AF:

0.283

AC:

408344

AN:

1443328

Hom.:

58870

Cov.:

AF XY:

0.283

AC XY:

202782

AN XY:

715744

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.200

Gnomad4 ASJ exome

AF:

0.293

Gnomad4 EAS exome

AF:

0.396

Gnomad4 SAS exome

AF:

0.261

Gnomad4 FIN exome

AF:

0.243

Gnomad4 NFE exome

AF:

0.288

Gnomad4 OTH exome

AF:

0.285

GnomAD4 genome

AF:

0.249

AC:

37883

AN:

152118

Hom.:

5061

Cov.:

AF XY:

0.245

AC XY:

18201

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.175

Gnomad4 AMR

AF:

0.215

Gnomad4 ASJ

AF:

0.292

Gnomad4 EAS

AF:

0.389

Gnomad4 SAS

AF:

0.268

Gnomad4 FIN

AF:

0.236

Gnomad4 NFE

AF:

0.287

Gnomad4 OTH

AF:

0.273

Alfa

AF:

0.274

Hom.:

3419

Bravo

AF:

0.246

TwinsUK

AF:

0.292

AC:

1084

ALSPAC

AF:

0.296

AC:

1142

ESP6500AA

AF:

0.164

AC:

653

ESP6500EA

AF:

0.256

AC:

2011

ExAC

AF:

0.269

AC:

31834

Asia WGS

AF:

0.306

AC:

1066

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

Microcephalic osteodysplastic primordial dwarfism type II

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

0.077

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.1

DANN

Benign

0.58

DEOGEN2

Benign

0.014

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.030

REVEL

Benign

0.0060

Sift

Benign

0.65

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.018

MPC

0.082

ClinPred

0.00030

GERP RS

-0.65

Varity_R

0.027

gMVP

0.18

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

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