21-46363881-T-C

Position:

• chr21-46363881-T-C

Variant summary

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

The ENST00000359568.10(PCNT):​c.2556T>C​(p.Ala852=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 1,612,428 control chromosomes in the GnomAD database, including 611,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58784 hom., cov: 33)
  • Exomes 𝑓: 0.87 (552706 hom.)
• Consequence: PCNT ENST00000359568.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.303

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=-0.96).
• BP6: Variant 21-46363881-T-C is Benign according to our data. Variant chr21-46363881-T-C is described in ClinVar as [Benign]. Clinvar id is 159572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46363881-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.303 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.2556T>C	p.Ala852=	synonymous_variant	14/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.2202T>C	p.Ala734=	synonymous_variant	14/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.2556T>C	p.Ala852=	synonymous_variant	14/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133554 AN: 152132 Hom.: 58738 Cov.: 33

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.788

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.881

GnomAD3 exomes AF: 0.854 AC: 210903 AN: 246928 Hom.: 90349 AF XY: 0.851 AC XY: 114434 AN XY: 134502

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.835

Gnomad ASJ exome AF: 0.888

Gnomad EAS exome AF: 0.817

Gnomad SAS exome AF: 0.783

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.874

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.869 AC: 1269348 AN: 1460178 Hom.: 552706 Cov.: 68 AF XY: 0.866 AC XY: 628910 AN XY: 726394

Gnomad4 AFR exome AF: 0.926

Gnomad4 AMR exome AF: 0.834

Gnomad4 ASJ exome AF: 0.889

Gnomad4 EAS exome AF: 0.779

Gnomad4 SAS exome AF: 0.789

Gnomad4 FIN exome AF: 0.842

Gnomad4 NFE exome AF: 0.879

Gnomad4 OTH exome AF: 0.870

GnomAD4 genome AF: 0.878 AC: 133659 AN: 152250 Hom.: 58784 Cov.: 33 AF XY: 0.872 AC XY: 64914 AN XY: 74444

Gnomad4 AFR AF: 0.927

Gnomad4 AMR AF: 0.841

Gnomad4 ASJ AF: 0.875

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.788

Gnomad4 FIN AF: 0.841

Gnomad4 NFE AF: 0.875

Gnomad4 OTH AF: 0.882

Alfa AF: 0.873 Hom.: 11820

Bravo AF: 0.882

Asia WGS AF: 0.803 AC: 2795 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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 provided Benign:3

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

PCNT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2024

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
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.4
DANN	Benign	0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs8131546; hg19: chr21-47783796; COSMIC: COSV64030319;