rs2249060

Positions:

chr21-46353263-C-T

Variant summary

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

The NM_006031.6(PCNT):c.1616C>T(p.Thr539Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,838 control chromosomes in the GnomAD database, including 14,670 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1357 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13313 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.244

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=0.0035569966).

BP6

Variant 21-46353263-C-T is Benign according to our data. Variant chr21-46353263-C-T is described in ClinVar as [Benign]. Clinvar id is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46353263-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.1616C>T	p.Thr539Ile	missense_variant	10/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.1262C>T	p.Thr421Ile	missense_variant	10/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.1616C>T	p.Thr539Ile	missense_variant	10/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19766

AN:

152074

Hom.:

1355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.123

GnomAD3 exomes

AF:

0.147

AC:

36930

AN:

251422

Hom.:

2974

AF XY:

0.150

AC XY:

20366

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.183

Gnomad SAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.130

AC:

190656

AN:

1461646

Hom.:

13313

Cov.:

AF XY:

0.134

AC XY:

97237

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.167

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.216

Gnomad4 SAS exome

AF:

0.209

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.120

Gnomad4 OTH exome

AF:

0.132

GnomAD4 genome

AF:

0.130

AC:

19788

AN:

152192

Hom.:

1357

Cov.:

AF XY:

0.136

AC XY:

10136

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.161

Gnomad4 ASJ

AF:

0.125

Gnomad4 EAS

AF:

0.192

Gnomad4 SAS

AF:

0.209

Gnomad4 FIN

AF:

0.159

Gnomad4 NFE

AF:

0.124

Gnomad4 OTH

AF:

0.122

Alfa

AF:

0.127

Hom.:

3362

Bravo

AF:

0.127

TwinsUK

AF:

0.122

AC:

452

ALSPAC

AF:

0.118

AC:

453

ESP6500AA

AF:

0.104

AC:

460

ESP6500EA

AF:

0.124

AC:

1070

ExAC

AF:

0.147

AC:

17838

Asia WGS

AF:

0.199

AC:

688

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.125

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.4

DANN

Benign

0.88

DEOGEN2

Benign

0.11

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.015

Sift

Benign

0.11

Sift4G

Benign

0.38

Polyphen

0.14

Vest4

0.027

MPC

0.14

ClinPred

0.0066

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.044

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