chr21-46334596-A-G

Position:

chr21-46334596-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_006031.6(PCNT):c.467A>G(p.His156Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 139,726 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H156Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 62 hom. )

Failed GnomAD Quality Control

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.595

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003022194).

BP6

Variant 21-46334596-A-G is Benign according to our data. Variant chr21-46334596-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159608.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr21-46334596-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.467A>G	p.His156Arg	missense_variant	3/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.113A>G	p.His38Arg	missense_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.467A>G	p.His156Arg	missense_variant	3/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

194

AN:

139612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000425

Gnomad ASJ

AF:

0.000905

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.000427

Gnomad FIN

AF:

0.000696

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00156

GnomAD3 exomes

AF:

0.00138

AC:

330

AN:

238690

Hom.:

AF XY:

0.00130

AC XY:

167

AN XY:

128936

show subpopulations

Gnomad AFR exome

AF:

0.000636

Gnomad AMR exome

AF:

0.000632

Gnomad ASJ exome

AF:

0.000926

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000198

Gnomad FIN exome

AF:

0.000812

Gnomad NFE exome

AF:

0.00241

Gnomad OTH exome

AF:

0.00206

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00617

AC:

8203

AN:

1330044

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

3846

AN XY:

663618

show subpopulations

Gnomad4 AFR exome

AF:

0.00148

Gnomad4 AMR exome

AF:

0.00374

Gnomad4 ASJ exome

AF:

0.00231

Gnomad4 EAS exome

AF:

0.000329

Gnomad4 SAS exome

AF:

0.000445

Gnomad4 FIN exome

AF:

0.00138

Gnomad4 NFE exome

AF:

0.00762

Gnomad4 OTH exome

AF:

0.00442

GnomAD4 genome

AF:

0.00140

AC:

195

AN:

139726

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

68688

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.000425

Gnomad4 ASJ

AF:

0.000905

Gnomad4 EAS

AF:

0.000393

Gnomad4 SAS

AF:

0.000428

Gnomad4 FIN

AF:

0.000696

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.00154

Alfa

AF:

0.0456

Hom.:

Bravo

AF:

0.0376

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0370

AC:

318

ExAC

AF:

0.000556

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2016	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	Eurofins Ntd Llc (ga)	May 19, 2016	- -

Microcephalic osteodysplastic primordial dwarfism type II

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.23

DANN

Benign

0.31

DEOGEN2

Benign

0.016

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00062

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.030

REVEL

Benign

0.023

Sift

Benign

0.45

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.084

MVP

0.20

MPC

0.099

ClinPred

0.0013

GERP RS

0.16

Varity_R

0.025

gMVP

0.015

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