rs138361417

Positions:

chr21-46367035-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006031.6(PCNT):c.3061C>T(p.Arg1021Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.65

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1271745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.3061C>T	p.Arg1021Trp	missense_variant	15/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 linkuse as main transcript	c.2707C>T	p.Arg903Trp	missense_variant	15/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.3061C>T	p.Arg1021Trp	missense_variant	15/47	1	NM_006031.6	ENSP00000352572	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251246

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000519

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 03, 2015

- -

PCNT-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The PCNT c.3061C>T variant is predicted to result in the amino acid substitution p.Arg1021Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 18, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1021 of the PCNT protein (p.Arg1021Trp). This variant is present in population databases (rs138361417, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PCNT-related conditions. ClinVar contains an entry for this variant (Variation ID: 436188). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Microcephalic osteodysplastic primordial dwarfism type II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 03, 2019

The PCNT c.3061C>T; p.Arg1021Trp variant (rs138361417), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 436188). It is observed in the general population at an overall frequency of 0.0068% (17/251246 alleles) in the Genome Aggregation Database. The arginine at codon 1021 is weakly conserved, but computational algorithms (PolyPhen-2: benign, SIFT: damaging) predict conflicting effects of this variants on protein structure/function. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.74

M_CAP

Benign

0.027

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.031

Sift4G

Uncertain

0.025

Polyphen

0.99

Vest4

0.24

MVP

0.62

MPC

0.093

ClinPred

0.083

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.058

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