21-46431722-G-A

Position:

chr21-46431722-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006031.6(PCNT):c.8258G>A(p.Arg2753His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,611,716 control chromosomes in the GnomAD database, including 2,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 223 hom., cov: 33)

Exomes 𝑓: 0.055 ( 2531 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.465

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=0.001970321).

BP6

Variant 21-46431722-G-A is Benign according to our data. Variant chr21-46431722-G-A is described in ClinVar as [Benign]. Clinvar id is 138610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431722-G-A is described in Lovd as [Benign]. Variant chr21-46431722-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.8258G>A	p.Arg2753His	missense_variant	38/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 linkuse as main transcript	c.7904G>A	p.Arg2635His	missense_variant	38/47		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.8258G>A	p.Arg2753His	missense_variant	38/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0479

AC:

7285

AN:

152204

Hom.:

224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0711

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.0848

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0638

Gnomad OTH

AF:

0.0497

GnomAD3 exomes

AF:

0.0462

AC:

11341

AN:

245422

Hom.:

311

AF XY:

0.0457

AC XY:

6092

AN XY:

133304

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.0221

Gnomad ASJ exome

AF:

0.0724

Gnomad EAS exome

AF:

0.000331

Gnomad SAS exome

AF:

0.0142

Gnomad FIN exome

AF:

0.0879

Gnomad NFE exome

AF:

0.0626

Gnomad OTH exome

AF:

0.0516

GnomAD4 exome

AF:

0.0553

AC:

80734

AN:

1459394

Hom.:

2531

Cov.:

AF XY:

0.0543

AC XY:

39407

AN XY:

726016

show subpopulations

Gnomad4 AFR exome

AF:

0.0250

Gnomad4 AMR exome

AF:

0.0240

Gnomad4 ASJ exome

AF:

0.0711

Gnomad4 EAS exome

AF:

0.000580

Gnomad4 SAS exome

AF:

0.0140

Gnomad4 FIN exome

AF:

0.0833

Gnomad4 NFE exome

AF:

0.0613

Gnomad4 OTH exome

AF:

0.0517

GnomAD4 genome

AF:

0.0479

AC:

7291

AN:

152322

Hom.:

223

Cov.:

AF XY:

0.0474

AC XY:

3528

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0266

Gnomad4 AMR

AF:

0.0334

Gnomad4 ASJ

AF:

0.0711

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.00911

Gnomad4 FIN

AF:

0.0848

Gnomad4 NFE

AF:

0.0638

Gnomad4 OTH

AF:

0.0491

Alfa

AF:

0.0552

Hom.:

210

Bravo

AF:

0.0434

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0602

AC:

232

ESP6500AA

AF:

0.0329

AC:

145

ESP6500EA

AF:

0.0624

AC:

537

ExAC

AF:

0.0461

AC:

5596

Asia WGS

AF:

0.0120

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.7

DANN

Benign

0.97

DEOGEN2

Benign

0.24

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.031

Sift

Benign

0.082

Sift4G

Uncertain

0.041

Polyphen

0.98

Vest4

0.064

MPC

0.42

ClinPred

0.011

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.18

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