chr21-46366579-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006031.6(PCNT):c.2610-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,612,214 control chromosomes in the GnomAD database, including 494,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 37953 hom., cov: 33)

Exomes 𝑓: 0.79 ( 456463 hom. )

Consequence

PCNT
NM_006031.6 splice_region, intron

Scores

Splicing: ADA: 0.00001390

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.361

Publications

25 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 (BayesDel_noAF=-0.81).

BP6

Variant 21-46366579-C-T is Benign according to our data. Variant chr21-46366579-C-T is described in ClinVar as [Benign]. Clinvar id is 159574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.2610-5C>T		splice_region_variant, intron_variant	Intron 14 of 46	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.2256-5C>T		splice_region_variant, intron_variant	Intron 14 of 46		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.2610-5C>T		splice_region_variant, intron_variant	Intron 14 of 46	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.690

AC:

104855

AN:

151932

Hom.:

37948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.452

Gnomad AMI

AF:

0.765

Gnomad AMR

AF:

0.742

Gnomad ASJ

AF:

0.789

Gnomad EAS

AF:

0.800

Gnomad SAS

AF:

0.697

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.787

Gnomad NFE

AF:

0.800

Gnomad OTH

AF:

0.714

GnomAD2 exomes

AF:

0.756

AC:

188682

AN:

249504

AF XY:

0.759

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.779

Gnomad ASJ exome

AF:

0.800

Gnomad EAS exome

AF:

0.813

Gnomad FIN exome

AF:

0.731

Gnomad NFE exome

AF:

0.801

Gnomad OTH exome

AF:

0.788

GnomAD4 exome

AF:

0.788

AC:

1150112

AN:

1460164

Hom.:

456463

Cov.:

AF XY:

0.785

AC XY:

570464

AN XY:

726542

show subpopulations

African (AFR)

AF:

0.432

AC:

14445

AN:

33428

American (AMR)

AF:

0.773

AC:

34552

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.803

AC:

20978

AN:

26128

East Asian (EAS)

AF:

0.777

AC:

30825

AN:

39694

South Asian (SAS)

AF:

0.704

AC:

60667

AN:

86188

European-Finnish (FIN)

AF:

0.738

AC:

39386

AN:

53338

Middle Eastern (MID)

AF:

0.759

AC:

4378

AN:

5768

European-Non Finnish (NFE)

AF:

0.809

AC:

898443

AN:

1110580

Other (OTH)

AF:

0.770

AC:

46438

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11494

22989

34483

45978

57472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.690

AC:

104887

AN:

152050

Hom.:

37953

Cov.:

AF XY:

0.687

AC XY:

51066

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.451

AC:

18706

AN:

41442

American (AMR)

AF:

0.743

AC:

11352

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.789

AC:

2738

AN:

3470

East Asian (EAS)

AF:

0.799

AC:

4118

AN:

5152

South Asian (SAS)

AF:

0.697

AC:

3356

AN:

4818

European-Finnish (FIN)

AF:

0.735

AC:

7781

AN:

10592

Middle Eastern (MID)

AF:

0.777

AC:

227

AN:

292

European-Non Finnish (NFE)

AF:

0.800

AC:

54408

AN:

67976

Other (OTH)

AF:

0.712

AC:

1503

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1400

2800

4200

5600

7000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.756

Hom.:

115613

Bravo

AF:

0.684

Asia WGS

AF:

0.691

AC:

2408

AN:

3478

EpiCase

AF:

0.804

EpiControl

AF:

0.804

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Benign:4

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. -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.8

(source)

DANN

Benign

0.47

PhyloP100

0.36

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0

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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chr21-46366579-C-T

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