21-46411844-C-T

Variant names:

Variant summary

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

The NM_006031.6(PCNT):c.5771C>T(p.Ala1924Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00693 in 1,558,970 control chromosomes in the GnomAD database, including 48 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0070 ( 45 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.32

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=0.0041799545).

BP6

Variant 21-46411844-C-T is Benign according to our data. Variant chr21-46411844-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46411844-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00597 (909/152346) while in subpopulation NFE AF= 0.00894 (608/68032). AF 95% confidence interval is 0.00835. There are 3 homozygotes in gnomad4. There are 403 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.5771C>T	p.Ala1924Val	missense_variant	Exon 28 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.5417C>T	p.Ala1806Val	missense_variant	Exon 28 of 47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.5771C>T	p.Ala1924Val	missense_variant	Exon 28 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00597

AC:

909

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00248

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00830

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00894

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00596

AC:

962

AN:

161328

Hom.:

AF XY:

0.00592

AC XY:

531

AN XY:

89740

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00687

Gnomad ASJ exome

AF:

0.00882

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00119

Gnomad FIN exome

AF:

0.00118

Gnomad NFE exome

AF:

0.00897

Gnomad OTH exome

AF:

0.00966

GnomAD4 exome

AF:

0.00703

AC:

9893

AN:

1406624

Hom.:

Cov.:

AF XY:

0.00704

AC XY:

4906

AN XY:

696660

show subpopulations

Gnomad4 AFR exome

AF:

0.00188

Gnomad4 AMR exome

AF:

0.00726

Gnomad4 ASJ exome

AF:

0.00812

Gnomad4 EAS exome

AF:

0.0000270

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00148

Gnomad4 NFE exome

AF:

0.00793

Gnomad4 OTH exome

AF:

0.00761

GnomAD4 genome

AF:

0.00597

AC:

909

AN:

152346

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

403

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.00829

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00894

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00722

Hom.:

Bravo

AF:

0.00672

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000549

AC:

ESP6500EA

AF:

0.00713

AC:

ExAC

AF:

0.00445

AC:

500

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCNT: BP4, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

Jan 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 11, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:2

Jul 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.11

DANN

Benign

0.47

DEOGEN2

Benign

0.021

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.11

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.21

REVEL

Benign

0.0050

Sift

Benign

0.78

Sift4G

Benign

0.67

Polyphen

0.0040

Vest4

0.046

MVP

0.27

MPC

0.33

ClinPred

0.00099

GERP RS

-5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.13

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