21-46430570-G-C

Position:

chr21-46430570-G-C

Variant summary

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

The NM_006031.6(PCNT):c.7977G>C(p.Gln2659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,559,684 control chromosomes in the GnomAD database, including 228,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19204 hom., cov: 33)

Exomes 𝑓: 0.54 ( 209449 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.90

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=2.4640954E-6).

BP6

Variant 21-46430570-G-C is Benign according to our data. Variant chr21-46430570-G-C is described in ClinVar as [Benign]. Clinvar id is 159670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46430570-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 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.7977G>C	p.Gln2659His	missense_variant	37/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 linkuse as main transcript	c.7623G>C	p.Gln2541His	missense_variant	37/47		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.7977G>C	p.Gln2659His	missense_variant	37/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.491

AC:

74529

AN:

151918

Hom.:

19196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.698

Gnomad AMR

AF:

0.481

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.533

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.533

GnomAD3 exomes

AF:

0.526

AC:

90059

AN:

171372

Hom.:

24287

AF XY:

0.533

AC XY:

48447

AN XY:

90846

show subpopulations

Gnomad AFR exome

AF:

0.329

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.650

Gnomad EAS exome

AF:

0.622

Gnomad SAS exome

AF:

0.529

Gnomad FIN exome

AF:

0.510

Gnomad NFE exome

AF:

0.558

Gnomad OTH exome

AF:

0.541

GnomAD4 exome

AF:

0.543

AC:

764307

AN:

1407648

Hom.:

209449

Cov.:

AF XY:

0.545

AC XY:

379032

AN XY:

695260

show subpopulations

Gnomad4 AFR exome

AF:

0.335

Gnomad4 AMR exome

AF:

0.440

Gnomad4 ASJ exome

AF:

0.651

Gnomad4 EAS exome

AF:

0.673

Gnomad4 SAS exome

AF:

0.535

Gnomad4 FIN exome

AF:

0.512

Gnomad4 NFE exome

AF:

0.547

Gnomad4 OTH exome

AF:

0.542

GnomAD4 genome

AF:

0.491

AC:

74577

AN:

152036

Hom.:

19204

Cov.:

AF XY:

0.489

AC XY:

36296

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.344

Gnomad4 AMR

AF:

0.481

Gnomad4 ASJ

AF:

0.657

Gnomad4 EAS

AF:

0.632

Gnomad4 SAS

AF:

0.534

Gnomad4 FIN

AF:

0.499

Gnomad4 NFE

AF:

0.554

Gnomad4 OTH

AF:

0.530

Alfa

AF:

0.524

Hom.:

6086

Bravo

AF:

0.484

TwinsUK

AF:

0.550

AC:

2041

ALSPAC

AF:

0.544

AC:

2097

ESP6500AA

AF:

0.342

AC:

1499

ESP6500EA

AF:

0.557

AC:

4764

ExAC

AF:

0.453

AC:

51092

Asia WGS

AF:

0.571

AC:

1985

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0020

DANN

Benign

0.89

DEOGEN2

Benign

0.19

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0000025

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

REVEL

Benign

0.083

Sift

Benign

0.093

Sift4G

Uncertain

0.032

Polyphen

0.031

Vest4

0.066

MutPred

0.16

Loss of stability (P = 0.1486);

MPC

0.34

ClinPred

0.021

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.078

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