rs117987006

Positions:

chr21-46389339-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006031.6(PCNT):c.3748C>T(p.Arg1250Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,614,182 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1250Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 3 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.267

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=0.0076660514).

BP6

Variant 21-46389339-C-T is Benign according to our data. Variant chr21-46389339-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46389339-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00249 (379/152292) while in subpopulation AMR AF= 0.00412 (63/15306). AF 95% confidence interval is 0.0033. There are 2 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.3748C>T	p.Arg1250Trp	missense_variant	19/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.3394C>T	p.Arg1132Trp	missense_variant	19/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.3748C>T	p.Arg1250Trp	missense_variant	19/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00961

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00231

AC:

580

AN:

251472

Hom.:

AF XY:

0.00215

AC XY:

292

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00790

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00224

AC:

3274

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1557

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000707

Gnomad4 FIN exome

AF:

0.00790

Gnomad4 NFE exome

AF:

0.00237

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00249

AC:

379

AN:

152292

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00961

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.00218

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00243

AC:

295

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -

PCNT-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.85

M_CAP

Benign

0.026

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.10

REVEL

Benign

0.067

Sift

Benign

0.048

Sift4G

Benign

0.089

Polyphen

0.97

Vest4

0.29

MVP

0.53

MPC

0.12

ClinPred

0.021

GERP RS

2.4

Varity_R

0.063

gMVP

0.10

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