rs60444527

chr21-46416302-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):c.6384A>G(p.Thr2128=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,613,756 control chromosomes in the GnomAD database, including 12,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4358 hom., cov: 32)
  • Exomes 𝑓: 0.082 (7719 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.488

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-46416302-A-G is Benign according to our data. Variant chr21-46416302-A-G is described in ClinVar as [Benign]. Clinvar id is 138623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416302-A-G is described in Lovd as [Likely_benign]. Variant chr21-46416302-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.488 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.6384A>G	p.Thr2128=	synonymous_variant	30/47	ENST00000359568.10
PCNT	NM_001315529.2	c.6030A>G	p.Thr2010=	synonymous_variant	30/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.6384A>G	p.Thr2128=	synonymous_variant	30/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26807 AN: 151920 Hom.: 4353 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0916

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.0958 AC: 24075 AN: 251426 Hom.: 2216 AF XY: 0.0904 AC XY: 12282 AN XY: 135894

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.0879

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0747

Gnomad OTH exome AF: 0.0823

GnomAD4 exome AF: 0.0817 AC: 119430 AN: 1461718 Hom.: 7719 Cov.: 34 AF XY: 0.0808 AC XY: 58786 AN XY: 727172

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.0597

Gnomad4 ASJ exome AF: 0.0849

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0849

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.0720

Gnomad4 OTH exome AF: 0.0974

GnomAD4 genome AF: 0.177 AC: 26845 AN: 152038 Hom.: 4358 Cov.: 32 AF XY: 0.173 AC XY: 12869 AN XY: 74326

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0865

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.0914

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0762

Gnomad4 OTH AF: 0.166

Alfa AF: 0.125 Hom.: 1014

Bravo AF: 0.187

Asia WGS AF: 0.103 AC: 357 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0705

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.13
Dann	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs60444527; hg19: chr21-47836216; COSMIC: COSV64029125; COSMIC: COSV64029125;