chr21-46431882-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006031.6(PCNT):c.8418G>A(p.Ala2806Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,908 control chromosomes in the GnomAD database, including 13,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2806A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1178 hom., cov: 34)

Exomes 𝑓: 0.13 ( 12653 hom. )

Consequence

PCNT
NM_006031.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.49

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 21-46431882-G-A is Benign according to our data. Variant chr21-46431882-G-A is described in ClinVar as Benign. ClinVar VariationId is 159673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.49 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.8418G>A	p.Ala2806Ala	synonymous_variant	Exon 38 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.8064G>A	p.Ala2688Ala	synonymous_variant	Exon 38 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.8418G>A	p.Ala2806Ala	synonymous_variant	Exon 38 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17958

AN:

152150

Hom.:

1179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0658

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.156

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.114

GnomAD2 exomes

AF:

0.141

AC:

35501

AN:

250904

AF XY:

0.145

show subpopulations

Gnomad AFR exome

AF:

0.0651

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.189

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.126

AC:

184748

AN:

1461640

Hom.:

12653

Cov.:

AF XY:

0.130

AC XY:

94283

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.0660

AC:

2210

AN:

33480

American (AMR)

AF:

0.159

AC:

7129

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

2883

AN:

26136

East Asian (EAS)

AF:

0.221

AC:

8787

AN:

39700

South Asian (SAS)

AF:

0.203

AC:

17475

AN:

86254

European-Finnish (FIN)

AF:

0.156

AC:

8306

AN:

53226

Middle Eastern (MID)

AF:

0.162

AC:

936

AN:

5768

European-Non Finnish (NFE)

AF:

0.116

AC:

129398

AN:

1111970

Other (OTH)

AF:

0.126

AC:

7624

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

11333

22666

34000

45333

56666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4720

9440

14160

18880

23600

<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:

0.118

AC:

17978

AN:

152268

Hom.:

1178

Cov.:

AF XY:

0.124

AC XY:

9222

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0660

AC:

2743

AN:

41574

American (AMR)

AF:

0.156

AC:

2392

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

431

AN:

3472

East Asian (EAS)

AF:

0.200

AC:

1033

AN:

5172

South Asian (SAS)

AF:

0.198

AC:

955

AN:

4826

European-Finnish (FIN)

AF:

0.157

AC:

1660

AN:

10596

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8297

AN:

68008

Other (OTH)

AF:

0.115

AC:

244

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

844

1688

2533

3377

4221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.121

Hom.:

989

Bravo

AF:

0.114

Asia WGS

AF:

0.202

AC:

701

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PCNT-related disorder

Benign:1

Jan 03, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.24

(source)

DANN

Benign

0.41

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(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