21-46432171-G-A

Position:

chr21-46432171-G-A

Variant summary

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

The NM_006031.6(PCNT):c.8707G>A(p.Ala2903Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0707 in 1,613,078 control chromosomes in the GnomAD database, including 4,377 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 305 hom., cov: 34)

Exomes 𝑓: 0.072 ( 4072 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.30

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=0.0019298196).

BP6

Variant 21-46432171-G-A is Benign according to our data. Variant chr21-46432171-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 159675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46432171-G-A is described in Lovd as [Benign]. Variant chr21-46432171-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.8707G>A	p.Ala2903Thr	missense_variant	38/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.8160+193G>A		intron_variant			NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.8707G>A	p.Ala2903Thr	missense_variant	38/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8584

AN:

152250

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.0597

Gnomad ASJ

AF:

0.0835

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.0741

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0801

Gnomad OTH

AF:

0.0713

GnomAD3 exomes

AF:

0.0610

AC:

15089

AN:

247396

Hom.:

571

AF XY:

0.0619

AC XY:

8323

AN XY:

134364

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0340

Gnomad ASJ exome

AF:

0.0892

Gnomad EAS exome

AF:

0.0152

Gnomad SAS exome

AF:

0.0433

Gnomad FIN exome

AF:

0.0745

Gnomad NFE exome

AF:

0.0828

Gnomad OTH exome

AF:

0.0695

GnomAD4 exome

AF:

0.0722

AC:

105536

AN:

1460710

Hom.:

4072

Cov.:

AF XY:

0.0715

AC XY:

51964

AN XY:

726584

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.0368

Gnomad4 ASJ exome

AF:

0.0867

Gnomad4 EAS exome

AF:

0.0126

Gnomad4 SAS exome

AF:

0.0458

Gnomad4 FIN exome

AF:

0.0760

Gnomad4 NFE exome

AF:

0.0796

Gnomad4 OTH exome

AF:

0.0638

GnomAD4 genome

AF:

0.0563

AC:

8582

AN:

152368

Hom.:

305

Cov.:

AF XY:

0.0560

AC XY:

4170

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0161

Gnomad4 AMR

AF:

0.0596

Gnomad4 ASJ

AF:

0.0835

Gnomad4 EAS

AF:

0.0100

Gnomad4 SAS

AF:

0.0418

Gnomad4 FIN

AF:

0.0741

Gnomad4 NFE

AF:

0.0801

Gnomad4 OTH

AF:

0.0710

Alfa

AF:

0.0769

Hom.:

795

Bravo

AF:

0.0533

TwinsUK

AF:

0.0841

AC:

312

ALSPAC

AF:

0.0791

AC:

305

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0828

AC:

712

ExAC

AF:

0.0612

AC:

7432

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.0819

EpiControl

AF:

0.0838

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely 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:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

PCNT-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

0.091

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.53

DEOGEN2

Benign

0.018

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.88

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.31

PROVEAN

Benign

0.070

REVEL

Benign

0.083

Sift

Benign

0.23

Sift4G

Benign

0.46

Polyphen

0.089

Vest4

0.056

MPC

0.36

ClinPred

0.017

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.058

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