rs61735822

Positions:

chr21-46334649-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.520A>G(p.Ile174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,568,000 control chromosomes in the GnomAD database, including 1,546 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 0.039 ( 128 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1418 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.64

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=0.0017138422).

BP6

Variant 21-46334649-A-G is Benign according to our data. Variant chr21-46334649-A-G is described in ClinVar as [Benign]. Clinvar id is 138613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46334649-A-G is described in Lovd as [Benign]. Variant chr21-46334649-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0721 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.520A>G	p.Ile174Val	missense_variant	3/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 linkuse as main transcript	c.166A>G	p.Ile56Val	missense_variant	3/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.520A>G	p.Ile174Val	missense_variant	3/47	1	NM_006031.6	ENSP00000352572	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5356

AN:

138672

Hom.:

130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0282

Gnomad AMI

AF:

0.0652

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.000407

Gnomad SAS

AF:

0.0198

Gnomad FIN

AF:

0.00611

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0480

Gnomad OTH

AF:

0.0547

GnomAD3 exomes

AF:

0.0322

AC:

8016

AN:

248896

Hom.:

244

AF XY:

0.0330

AC XY:

4443

AN XY:

134656

show subpopulations

Gnomad AFR exome

AF:

0.0197

Gnomad AMR exome

AF:

0.0263

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0155

Gnomad FIN exome

AF:

0.00704

Gnomad NFE exome

AF:

0.0437

Gnomad OTH exome

AF:

0.0433

GnomAD4 exome

AF:

0.0352

AC:

50271

AN:

1429206

Hom.:

1418

Cov.:

AF XY:

0.0353

AC XY:

25108

AN XY:

711208

show subpopulations

Gnomad4 AFR exome

AF:

0.0205

Gnomad4 AMR exome

AF:

0.0265

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.000281

Gnomad4 SAS exome

AF:

0.0142

Gnomad4 FIN exome

AF:

0.00816

Gnomad4 NFE exome

AF:

0.0380

Gnomad4 OTH exome

AF:

0.0388

GnomAD4 genome

AF:

0.0386

AC:

5354

AN:

138794

Hom.:

128

Cov.:

AF XY:

0.0360

AC XY:

2449

AN XY:

68016

show subpopulations

Gnomad4 AFR

AF:

0.0282

Gnomad4 AMR

AF:

0.0394

Gnomad4 ASJ

AF:

0.125

Gnomad4 EAS

AF:

0.000408

Gnomad4 SAS

AF:

0.0201

Gnomad4 FIN

AF:

0.00611

Gnomad4 NFE

AF:

0.0480

Gnomad4 OTH

AF:

0.0530

Alfa

AF:

0.0460

Hom.:

TwinsUK

AF:

0.0448

AC:

166

ALSPAC

AF:

0.0379

AC:

146

ESP6500AA

AF:

0.0247

AC:

109

ESP6500EA

AF:

0.0557

AC:

479

ExAC

AF:

0.0328

AC:

3969

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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: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

0.076

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0050

DANN

Benign

0.16

DEOGEN2

Benign

0.014

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00039

LIST_S2

Benign

0.16

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.18

REVEL

Benign

0.010

Sift

Benign

0.24

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.033

MPC

0.068

ClinPred

0.0043

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.023

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