rs2839227

Positions:

chr21-46366609-A-G

Variant summary

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

The NM_006031.6(PCNT):c.2635A>G(p.Thr879Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,858 control chromosomes in the GnomAD database, including 29,428 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 0.26 ( 7074 hom., cov: 33)

Exomes 𝑓: 0.16 ( 22354 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.77

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:

PCNT (HGNC:):

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=7.278025E-4).

BP6

Variant 21-46366609-A-G is Benign according to our data. Variant chr21-46366609-A-G is described in ClinVar as [Benign]. Clinvar id is 159575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46366609-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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.2635A>G	p.Thr879Ala	missense_variant	15/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 linkuse as main transcript	c.2281A>G	p.Thr761Ala	missense_variant	15/47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.2635A>G	p.Thr879Ala	missense_variant	15/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39424

AN:

152004

Hom.:

7049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.510

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.137

Gnomad OTH

AF:

0.237

GnomAD3 exomes

AF:

0.197

AC:

49393

AN:

250338

Hom.:

6216

AF XY:

0.196

AC XY:

26532

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.518

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.187

Gnomad SAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.158

AC:

230292

AN:

1461736

Hom.:

22354

Cov.:

AF XY:

0.161

AC XY:

117162

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.532

Gnomad4 AMR exome

AF:

0.204

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.223

Gnomad4 SAS exome

AF:

0.282

Gnomad4 FIN exome

AF:

0.178

Gnomad4 NFE exome

AF:

0.131

Gnomad4 OTH exome

AF:

0.179

GnomAD4 genome

AF:

0.260

AC:

39503

AN:

152122

Hom.:

7074

Cov.:

AF XY:

0.263

AC XY:

19564

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.510

Gnomad4 AMR

AF:

0.223

Gnomad4 ASJ

AF:

0.141

Gnomad4 EAS

AF:

0.199

Gnomad4 SAS

AF:

0.294

Gnomad4 FIN

AF:

0.181

Gnomad4 NFE

AF:

0.137

Gnomad4 OTH

AF:

0.240

Alfa

AF:

0.162

Hom.:

6661

Bravo

AF:

0.270

TwinsUK

AF:

0.132

AC:

491

ALSPAC

AF:

0.129

AC:

497

ESP6500AA

AF:

0.501

AC:

2199

ESP6500EA

AF:

0.136

AC:

1168

ExAC

AF:

0.204

AC:

24797

Asia WGS

AF:

0.296

AC:

1027

AN:

3478

EpiCase

AF:

0.141

EpiControl

AF:

0.141

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- -
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 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.097

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.37

MetaRNN

Benign

0.00073

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.0

REVEL

Benign

0.047

Sift

Benign

0.31

Sift4G

Benign

0.56

Polyphen

0.17

Vest4

0.10

MPC

0.28

ClinPred

0.012

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.046

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