rs2073376

Positions:

• chr21-46431839-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):​c.8375A>G​(p.Gln2792Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,546 control chromosomes in the GnomAD database, including 322,770 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 0.67 (34980 hom., cov: 34)
  • Exomes 𝑓: 0.63 (287790 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0810

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.886558E-7).
• BP6: Variant 21-46431839-A-G is Benign according to our data. Variant chr21-46431839-A-G is described in ClinVar as [Benign]. Clinvar id is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431839-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.8375A>G	p.Gln2792Arg	missense_variant	38/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.8021A>G	p.Gln2674Arg	missense_variant	38/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.8375A>G	p.Gln2792Arg	missense_variant	38/47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102083 AN: 152028 Hom.: 34935 Cov.: 34

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.695

GnomAD3 exomes AF: 0.627 AC: 156951 AN: 250436 Hom.: 50038 AF XY: 0.629 AC XY: 85209 AN XY: 135434

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.483

Gnomad ASJ exome AF: 0.735

Gnomad EAS exome AF: 0.633

Gnomad SAS exome AF: 0.622

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.639

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.625 AC: 913994 AN: 1461402 Hom.: 287790 Cov.: 71 AF XY: 0.627 AC XY: 455793 AN XY: 727008

Gnomad4 AFR exome AF: 0.804

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.735

Gnomad4 EAS exome AF: 0.674

Gnomad4 SAS exome AF: 0.621

Gnomad4 FIN exome AF: 0.617

Gnomad4 NFE exome AF: 0.620

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.672 AC: 102180 AN: 152144 Hom.: 34980 Cov.: 34 AF XY: 0.666 AC XY: 49559 AN XY: 74368

Gnomad4 AFR AF: 0.791

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.743

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.606

Gnomad4 NFE AF: 0.631

Gnomad4 OTH AF: 0.696

Alfa AF: 0.639 Hom.: 76028

Bravo AF: 0.675

TwinsUK AF: 0.616 AC: 2284

ALSPAC AF: 0.617 AC: 2376

ESP6500AA AF: 0.792 AC: 3491

ESP6500EA AF: 0.640 AC: 5507

ExAC AF: 0.639 AC: 77537

Asia WGS AF: 0.679 AC: 2360 AN: 3478

EpiCase AF: 0.635

EpiControl AF: 0.645

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Benign:4

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

not provided Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2014	- -

PCNT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.11
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.087
ClinPred		0.0013	T
GERP RS		2.3
Varity_R		0.016
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

Other links and lift over

dbSNP: rs2073376; hg19: chr21-47851753; COSMIC: COSV64028610;