chr21-46416208-T-C

Position:

chr21-46416208-T-C

Variant summary

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

The NM_006031.6(PCNT):c.6290T>C(p.Leu2097Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,614,020 control chromosomes in the GnomAD database, including 12,097 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. L2097L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 4397 hom., cov: 32)

Exomes 𝑓: 0.082 ( 7700 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.677

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=2.3597479E-4).

BP6

Variant 21-46416208-T-C is Benign according to our data. Variant chr21-46416208-T-C is described in ClinVar as [Benign]. Clinvar id is 138621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416208-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 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.6290T>C	p.Leu2097Pro	missense_variant	30/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.5936T>C	p.Leu1979Pro	missense_variant	30/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.6290T>C	p.Leu2097Pro	missense_variant	30/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26876

AN:

152062

Hom.:

4392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0944

Gnomad ASJ

AF:

0.0864

Gnomad EAS

AF:

0.00558

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0762

Gnomad OTH

AF:

0.163

GnomAD3 exomes

AF:

0.0958

AC:

24089

AN:

251432

Hom.:

2224

AF XY:

0.0904

AC XY:

12289

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.0551

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.00315

Gnomad SAS exome

AF:

0.0880

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.0748

Gnomad OTH exome

AF:

0.0823

GnomAD4 exome

AF:

0.0817

AC:

119448

AN:

1461840

Hom.:

7700

Cov.:

AF XY:

0.0808

AC XY:

58794

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.456

Gnomad4 AMR exome

AF:

0.0596

Gnomad4 ASJ exome

AF:

0.0849

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.0849

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.0720

Gnomad4 OTH exome

AF:

0.0973

GnomAD4 genome

AF:

0.177

AC:

26914

AN:

152180

Hom.:

4397

Cov.:

AF XY:

0.174

AC XY:

12916

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.434

Gnomad4 AMR

AF:

0.0942

Gnomad4 ASJ

AF:

0.0864

Gnomad4 EAS

AF:

0.00559

Gnomad4 SAS

AF:

0.0920

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.0762

Gnomad4 OTH

AF:

0.167

Alfa

AF:

0.0901

Hom.:

2576

Bravo

AF:

0.187

TwinsUK

AF:

0.0653

AC:

242

ALSPAC

AF:

0.0724

AC:

279

ESP6500AA

AF:

0.434

AC:

1913

ESP6500EA

AF:

0.0758

AC:

652

ExAC

AF:

0.104

AC:

12576

Asia WGS

AF:

0.104

AC:

362

AN:

3478

EpiCase

AF:

0.0702

EpiControl

AF:

0.0706

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

0.053

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

DANN

Benign

0.30

DEOGEN2

Benign

0.020

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.16

MetaRNN

Benign

0.00024

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

0.53

REVEL

Benign

0.024

Sift

Benign

0.34

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.019

MPC

0.13

ClinPred

0.00077

GERP RS

-1.5

Varity_R

0.049

gMVP

0.074

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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