rs35044802

Positions:

chr21-46388857-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.3580G>A(p.Ala1194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,608,322 control chromosomes in the GnomAD database, including 1,611 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 0.035 ( 132 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1479 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.630

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=0.001982838).

BP6

Variant 21-46388857-G-A is Benign according to our data. Variant chr21-46388857-G-A is described in ClinVar as [Benign]. Clinvar id is 159590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46388857-G-A is described in Lovd as [Benign]. Variant chr21-46388857-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0773 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.3580G>A	p.Ala1194Thr	missense_variant	18/47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 linkuse as main transcript	c.3226G>A	p.Ala1076Thr	missense_variant	18/47		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.3580G>A	p.Ala1194Thr	missense_variant	18/47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5277

AN:

152174

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.0359

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0445

Gnomad OTH

AF:

0.0498

GnomAD3 exomes

AF:

0.0360

AC:

8749

AN:

243052

Hom.:

255

AF XY:

0.0364

AC XY:

4815

AN XY:

132290

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.0279

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.0000553

Gnomad SAS exome

AF:

0.0168

Gnomad FIN exome

AF:

0.00802

Gnomad NFE exome

AF:

0.0486

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0403

AC:

58616

AN:

1456030

Hom.:

1479

Cov.:

AF XY:

0.0403

AC XY:

29160

AN XY:

724472

show subpopulations

Gnomad4 AFR exome

AF:

0.0233

Gnomad4 AMR exome

AF:

0.0301

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0183

Gnomad4 FIN exome

AF:

0.00892

Gnomad4 NFE exome

AF:

0.0435

Gnomad4 OTH exome

AF:

0.0431

GnomAD4 genome

AF:

0.0346

AC:

5276

AN:

152292

Hom.:

132

Cov.:

AF XY:

0.0325

AC XY:

2417

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0232

Gnomad4 AMR

AF:

0.0359

Gnomad4 ASJ

AF:

0.116

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.0445

Gnomad4 OTH

AF:

0.0483

Alfa

AF:

0.0506

Hom.:

222

Bravo

AF:

0.0379

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.0544

AC:

468

ExAC

AF:

0.0349

AC:

4229

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.98

DANN

Benign

0.96

DEOGEN2

Benign

0.018

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.020

REVEL

Benign

0.055

Sift

Benign

0.72

Sift4G

Benign

0.20

Polyphen

0.34

Vest4

0.019

MPC

0.078

ClinPred

0.0041

GERP RS

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.051

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