21-46388764-C-T

Position:

chr21-46388764-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.3487C>T(p.Arg1163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,632 control chromosomes in the GnomAD database, including 15,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1285 hom., cov: 33)

Exomes 𝑓: 0.13 ( 14021 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.242

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=0.005921036).

BP6

Variant 21-46388764-C-T is Benign according to our data. Variant chr21-46388764-C-T is described in ClinVar as [Benign]. Clinvar id is 159589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46388764-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 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.3487C>T	p.Arg1163Cys	missense_variant	18/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 linkuse as main transcript	c.3133C>T	p.Arg1045Cys	missense_variant	18/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.3487C>T	p.Arg1163Cys	missense_variant	18/47	1	NM_006031.6	ENSP00000352572	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18698

AN:

152082

Hom.:

1284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0690

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.120

GnomAD3 exomes

AF:

0.148

AC:

37018

AN:

250838

Hom.:

2993

AF XY:

0.151

AC XY:

20542

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.0672

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.189

Gnomad SAS exome

AF:

0.219

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.134

AC:

195571

AN:

1461432

Hom.:

14021

Cov.:

AF XY:

0.137

AC XY:

99781

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.0685

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.222

Gnomad4 SAS exome

AF:

0.214

Gnomad4 FIN exome

AF:

0.160

Gnomad4 NFE exome

AF:

0.124

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.123

AC:

18718

AN:

152200

Hom.:

1285

Cov.:

AF XY:

0.129

AC XY:

9564

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0692

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.125

Gnomad4 EAS

AF:

0.201

Gnomad4 SAS

AF:

0.212

Gnomad4 FIN

AF:

0.161

Gnomad4 NFE

AF:

0.129

Gnomad4 OTH

AF:

0.121

Alfa

AF:

0.130

Hom.:

2179

Bravo

AF:

0.118

TwinsUK

AF:

0.128

AC:

475

ALSPAC

AF:

0.121

AC:

466

ESP6500AA

AF:

0.0654

AC:

288

ESP6500EA

AF:

0.129

AC:

1110

ExAC

AF:

0.147

AC:

17865

Asia WGS

AF:

0.205

AC:

711

AN:

3478

EpiCase

AF:

0.130

EpiControl

AF:

0.130

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	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Genetic Services Laboratory, University of Chicago	May 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2016	- -

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

0.15

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.099

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.18

MPC

0.46

ClinPred

0.063

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.16

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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