rs61735812

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006031.6(PCNT):c.6739C>T(p.His2247Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,563,558 control chromosomes in the GnomAD database, including 127 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H2247H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 23 hom., cov: 32)

Exomes 𝑓: 0.010 ( 104 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.182

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025939345).

BP6

Variant 21-46416657-C-T is Benign according to our data. Variant chr21-46416657-C-T is described in ClinVar as Benign. ClinVar VariationId is 138627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2299/152288) while in subpopulation AFR AF = 0.0253 (1050/41568). AF 95% confidence interval is 0.024. There are 23 homozygotes in GnomAd4. There are 1149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.6739C>T	p.His2247Tyr	missense_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.6385C>T	p.His2129Tyr	missense_variant	Exon 30 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.6739C>T	p.His2247Tyr	missense_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2293

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0212

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0118

AC:

2409

AN:

204038

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.000231

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.0120

GnomAD4 exome

AF:

0.0101

AC:

14198

AN:

1411270

Hom.:

104

Cov.:

AF XY:

0.0100

AC XY:

6991

AN XY:

696664

show subpopulations

African (AFR)

AF:

0.0288

AC:

922

AN:

32054

American (AMR)

AF:

0.00984

AC:

383

AN:

38920

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

275

AN:

22186

East Asian (EAS)

AF:

0.000102

AC:

AN:

39378

South Asian (SAS)

AF:

0.00557

AC:

427

AN:

76648

European-Finnish (FIN)

AF:

0.0199

AC:

992

AN:

49968

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

0.00960

AC:

10448

AN:

1088534

Other (OTH)

AF:

0.0114

AC:

663

AN:

58116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

821

1641

2462

3282

4103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.0151

AC:

2299

AN:

152288

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1149

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0253

AC:

1050

AN:

41568

American (AMR)

AF:

0.0123

AC:

189

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00559

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0212

AC:

225

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

708

AN:

68008

Other (OTH)

AF:

0.0208

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

122

244

367

489

611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0117

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.0203

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.0114

AC:

1374

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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 09, 2014

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

0.083

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.2

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.033

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

PhyloP100

0.18

PrimateAI

Benign

0.27

PROVEAN

Benign

0.64

REVEL

Benign

0.038

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.78

Vest4

0.062

MPC

0.22

ClinPred

0.0022

GERP RS

-1.6

Varity_R

0.037

gMVP

0.11

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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