rs61735814

Positions:

chr21-46422075-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.7130C>T(p.Pro2377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,866 control chromosomes in the GnomAD database, including 2,622 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. P2377P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.041 ( 195 hom., cov: 33)

Exomes 𝑓: 0.054 ( 2427 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.50

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=0.0017070472).

BP6

Variant 21-46422075-C-T is Benign according to our data. Variant chr21-46422075-C-T is described in ClinVar as [Benign]. Clinvar id is 138631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46422075-C-T is described in Lovd as [Benign]. Variant chr21-46422075-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 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.7130C>T	p.Pro2377Leu	missense_variant	32/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.6776C>T	p.Pro2259Leu	missense_variant	32/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.7130C>T	p.Pro2377Leu	missense_variant	32/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

6311

AN:

152194

Hom.:

196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00982

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0261

Gnomad ASJ

AF:

0.0565

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.0851

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0625

Gnomad OTH

AF:

0.0382

GnomAD3 exomes

AF:

0.0431

AC:

10807

AN:

251014

Hom.:

285

AF XY:

0.0430

AC XY:

5840

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.00857

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.0570

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0139

Gnomad FIN exome

AF:

0.0864

Gnomad NFE exome

AF:

0.0608

Gnomad OTH exome

AF:

0.0464

GnomAD4 exome

AF:

0.0538

AC:

78595

AN:

1461554

Hom.:

2427

Cov.:

AF XY:

0.0528

AC XY:

38378

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00777

Gnomad4 AMR exome

AF:

0.0198

Gnomad4 ASJ exome

AF:

0.0554

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0135

Gnomad4 FIN exome

AF:

0.0834

Gnomad4 NFE exome

AF:

0.0606

Gnomad4 OTH exome

AF:

0.0473

GnomAD4 genome

AF:

0.0414

AC:

6309

AN:

152312

Hom.:

195

Cov.:

AF XY:

0.0408

AC XY:

3042

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00979

Gnomad4 AMR

AF:

0.0261

Gnomad4 ASJ

AF:

0.0565

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00932

Gnomad4 FIN

AF:

0.0851

Gnomad4 NFE

AF:

0.0625

Gnomad4 OTH

AF:

0.0378

Alfa

AF:

0.0535

Hom.:

277

Bravo

AF:

0.0360

TwinsUK

AF:

0.0537

AC:

199

ALSPAC

AF:

0.0597

AC:

230

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.0609

AC:

524

ExAC

AF:

0.0433

AC:

5263

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0541

EpiControl

AF:

0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

0.085

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.085

DANN

Benign

0.63

DEOGEN2

Benign

0.027

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

REVEL

Benign

0.086

Sift

Benign

0.23

Sift4G

Benign

0.13

Polyphen

0.76

Vest4

0.031

MPC

0.41

ClinPred

0.012

GERP RS

-7.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.011

gMVP

0.094

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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