NM_006031.6:c.427C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006031.6(PCNT):c.427C>T(p.Arg143Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,598,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.06

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

microcephalic osteodysplastic primordial dwarfism type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Moyamoya disease
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

PCNT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019827008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 3 of 47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 link	c.73C>T	p.Arg25Cys	missense_variant	Exon 3 of 47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 3 of 47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000328

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:

0.000294

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000203

AC:

AN:

251442

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000281

AC:

406

AN:

1446864

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

203

AN XY:

719604

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

32856

American (AMR)

AF:

0.000654

AC:

AN:

44310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25552

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39562

South Asian (SAS)

AF:

0.00

AC:

AN:

85654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.000327

AC:

360

AN:

1101474

Other (OTH)

AF:

0.000185

AC:

AN:

59530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000224

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41374

American (AMR)

AF:

0.000328

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

67978

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCNT-related disorder

Uncertain:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PCNT c.427C>T variant is predicted to result in the amino acid substitution p.Arg143Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.076% of alleles in individuals of Latino descent in gnomAD. Of note, a different variant impacting the same amino acid residue (p.Arg143His) has been reported as de novo in at least one patient with autism (Family ID 13863 in Supplemental Table 2, Iossifov et al. 2014. PubMed ID: 25363768; Table S2, Turner et al. 2019. PubMed ID: 31785789). Although we suspect that this variant may be benign, 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

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 143 of the PCNT protein (p.Arg143Cys). This variant is present in population databases (rs201176638, gnomAD 0.06%). 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: 159598). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.1

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.026

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.50

M_CAP

Benign

0.0031

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.1

PhyloP100

-1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.77

REVEL

Benign

0.089

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.015

Polyphen

0.99

Vest4

0.13

MVP

0.33

MPC

0.11

ClinPred

0.015

GERP RS

-0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.091

gMVP

0.051

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over