rs4818842

Positions:

chr21-46438335-A-G

Variant summary

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

The NM_006031.6(PCNT):c.9271A>G(p.Ser3091Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0256 in 1,613,794 control chromosomes in the GnomAD database, including 770 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 0.025 ( 90 hom., cov: 33)

Exomes 𝑓: 0.026 ( 680 hom. )

Consequence

PCNT
NM_006031.6 missense, splice_region

Scores

Splicing: ADA: 0.2499

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.79

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:

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=0.0025025606).

BP6

Variant 21-46438335-A-G is Benign according to our data. Variant chr21-46438335-A-G is described in ClinVar as [Benign]. Clinvar id is 138614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46438335-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.9271A>G	p.Ser3091Gly	missense_variant, splice_region_variant	41/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.8680A>G	p.Ser2894Gly	missense_variant, splice_region_variant	41/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.9271A>G	p.Ser3091Gly	missense_variant, splice_region_variant	41/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3841

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0750

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.0434

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0282

GnomAD3 exomes

AF:

0.0336

AC:

8447

AN:

251206

Hom.:

262

AF XY:

0.0313

AC XY:

4251

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0997

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.00283

Gnomad SAS exome

AF:

0.0220

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0262

Gnomad OTH exome

AF:

0.0298

GnomAD4 exome

AF:

0.0256

AC:

37476

AN:

1461482

Hom.:

680

Cov.:

AF XY:

0.0255

AC XY:

18564

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00394

Gnomad4 AMR exome

AF:

0.0991

Gnomad4 ASJ exome

AF:

0.0137

Gnomad4 EAS exome

AF:

0.00582

Gnomad4 SAS exome

AF:

0.0210

Gnomad4 FIN exome

AF:

0.0408

Gnomad4 NFE exome

AF:

0.0242

Gnomad4 OTH exome

AF:

0.0224

GnomAD4 genome

AF:

0.0252

AC:

3843

AN:

152312

Hom.:

Cov.:

AF XY:

0.0269

AC XY:

2002

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00483

Gnomad4 AMR

AF:

0.0752

Gnomad4 ASJ

AF:

0.0144

Gnomad4 EAS

AF:

0.00309

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.0434

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0279

Alfa

AF:

0.0243

Hom.:

119

Bravo

AF:

0.0267

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0235

AC:

202

ExAC

AF:

0.0307

AC:

3726

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 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

0.062

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.045

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

REVEL

Benign

0.069

Sift

Benign

0.20

Sift4G

Benign

0.072

Polyphen

0.82

Vest4

0.037

MPC

0.21

ClinPred

0.028

GERP RS

5.0

Varity_R

0.062

gMVP

0.028

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.25

dbscSNV1_RF

Benign

0.23

SpliceAI score (max)

0.15

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