rs145055342

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006031.6(PCNT):c.4109G>A(p.Arg1370Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,596,248 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R1370W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00056 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -1.98

Publications

4 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004022807).

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.4109G>A	p.Arg1370Gln	missense_variant	Exon 21 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.3755G>A	p.Arg1252Gln	missense_variant	Exon 21 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.4109G>A	p.Arg1370Gln	missense_variant	Exon 21 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000328

AC:

AN:

213462

AF XY:

0.000303

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.000444

Gnomad OTH exome

AF:

0.000925

GnomAD4 exome

AF:

0.000281

AC:

406

AN:

1443930

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

184

AN XY:

716324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

41560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25708

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39086

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83028

European-Finnish (FIN)

AF:

0.000961

AC:

AN:

52012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000304

AC:

336

AN:

1103746

Other (OTH)

AF:

0.000301

AC:

AN:

59748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

115

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:

0.000565

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000322

Hom.:

Bravo

AF:

0.000842

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000373

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 22, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2024

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 glutamine, which is neutral and polar, at codon 1370 of the PCNT protein (p.Arg1370Gln). This variant is present in population databases (rs145055342, gnomAD 0.1%). 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: 195605). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:2

Jun 19, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCNT-related disorder

Uncertain:1

Apr 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PCNT c.4109G>A variant is predicted to result in the amino acid substitution p.Arg1370Gln. To our knowledge, this variant has not been reported in individuals with PCNT-associated disorders in the literature. This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too common to be an undocumented primary cause of disease. Although we suspect this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0060

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.014

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.32

PhyloP100

-2.0

PrimateAI

Benign

0.20

PROVEAN

Benign

1.1

REVEL

Benign

0.028

Sift

Benign

0.84

Sift4G

Benign

0.67

Polyphen

0.024

Vest4

0.079

MVP

0.37

MPC

0.093

ClinPred

0.011

GERP RS

-10

Varity_R

0.013

gMVP

0.013

Mutation Taster

=97/3

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