rs61735825

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_006031.6(PCNT):c.467A>G(p.His156Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 139,726 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H156Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 62 hom. )

Failed GnomAD Quality Control

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.595

Publications

12 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003022194).

BP6

Variant 21-46334596-A-G is Benign according to our data. Variant chr21-46334596-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159608.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.467A>G	p.His156Arg	missense_variant	Exon 3 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.113A>G	p.His38Arg	missense_variant	Exon 3 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.467A>G	p.His156Arg	missense_variant	Exon 3 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

194

AN:

139612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000425

Gnomad ASJ

AF:

0.000905

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.000427

Gnomad FIN

AF:

0.000696

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00156

GnomAD2 exomes

AF:

0.00138

AC:

330

AN:

238690

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.000636

Gnomad AMR exome

AF:

0.000632

Gnomad ASJ exome

AF:

0.000926

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000812

Gnomad NFE exome

AF:

0.00241

Gnomad OTH exome

AF:

0.00206

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00617

AC:

8203

AN:

1330044

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

3846

AN XY:

663618

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00148

AC:

AN:

32382

American (AMR)

AF:

0.00374

AC:

159

AN:

42546

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

24684

East Asian (EAS)

AF:

0.000329

AC:

AN:

39496

South Asian (SAS)

AF:

0.000445

AC:

AN:

85328

European-Finnish (FIN)

AF:

0.00138

AC:

AN:

50892

Middle Eastern (MID)

AF:

0.000888

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00762

AC:

7568

AN:

993640

Other (OTH)

AF:

0.00442

AC:

245

AN:

55444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.269

Heterozygous variant carriers

900

1799

2699

3598

4498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.00140

AC:

195

AN:

139726

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

68688

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

39128

American (AMR)

AF:

0.000425

AC:

AN:

14134

Ashkenazi Jewish (ASJ)

AF:

0.000905

AC:

AN:

3314

East Asian (EAS)

AF:

0.000393

AC:

AN:

5086

South Asian (SAS)

AF:

0.000428

AC:

AN:

4676

European-Finnish (FIN)

AF:

0.000696

AC:

AN:

10054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00184

AC:

111

AN:

60208

Other (OTH)

AF:

0.00154

AC:

AN:

1948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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:

0.0456

Hom.:

Bravo

AF:

0.0376

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0370

AC:

318

ExAC

AF:

0.000556

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2016

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. -

Microcephalic osteodysplastic primordial dwarfism type II

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.23

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.016

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00062

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.69

PhyloP100

-0.59

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.030

REVEL

Benign

0.023

Sift

Benign

0.45

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.084

MVP

0.20

MPC

0.099

ClinPred

0.0013

GERP RS

0.16

Varity_R

0.025

gMVP

0.015

Mutation Taster

=99/1

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