rs35848602

Positions:

chr21-46418268-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006031.6(PCNT):c.6986C>G(p.Pro2329Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,608,660 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 16 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.294

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 links:

PCNT (HGNC:):

PCNT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044974685).

BP6

Variant 21-46418268-C-G is Benign according to our data. Variant chr21-46418268-C-G is described in ClinVar as [Benign]. Clinvar id is 159647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46418268-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00597 (910/152320) while in subpopulation AFR AF= 0.0152 (632/41556). AF 95% confidence interval is 0.0142. There are 7 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.6986C>G	p.Pro2329Arg	missense_variant	31/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 linkuse as main transcript	c.6632C>G	p.Pro2211Arg	missense_variant	31/47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.6986C>G	p.Pro2329Arg	missense_variant	31/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00597

AC:

909

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00739

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00289

AC:

727

AN:

251256

Hom.:

AF XY:

0.00248

AC XY:

337

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.00391

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00146

AC:

2130

AN:

1456340

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1011

AN XY:

724954

show subpopulations

Gnomad4 AFR exome

AF:

0.0145

Gnomad4 AMR exome

AF:

0.00409

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000719

Gnomad4 OTH exome

AF:

0.00360

GnomAD4 genome

AF:

0.00597

AC:

910

AN:

152320

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.00738

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.00382

Hom.:

Bravo

AF:

0.00697

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00282

AC:

342

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 04, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.94

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.039

Sift

Benign

0.13

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.33

MVP

0.51

MPC

0.44

ClinPred

0.034

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over