rs9983522

chr21-46431882-G-A

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.8418G>A(p.Ala2806=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,908 control chromosomes in the GnomAD database, including 13,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2806A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1178 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12653 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.49

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=-0.85).
• BP6: Variant 21-46431882-G-A is Benign according to our data. Variant chr21-46431882-G-A is described in ClinVar as [Benign]. Clinvar id is 159673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46431882-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.8418G>A	p.Ala2806=	synonymous_variant	38/47	ENST00000359568.10
PCNT	NM_001315529.2	c.8064G>A	p.Ala2688=	synonymous_variant	38/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.8418G>A	p.Ala2806=	synonymous_variant	38/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17958 AN: 152150 Hom.: 1179 Cov.: 34

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.141 AC: 35501 AN: 250904 Hom.: 2774 AF XY: 0.145 AC XY: 19640 AN XY: 135646

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.126 AC: 184748 AN: 1461640 Hom.: 12653 Cov.: 40 AF XY: 0.130 AC XY: 94283 AN XY: 727118

Gnomad4 AFR exome AF: 0.0660

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.118 AC: 17978 AN: 152268 Hom.: 1178 Cov.: 34 AF XY: 0.124 AC XY: 9222 AN XY: 74442

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.115

Alfa AF: 0.118 Hom.: 580

Bravo AF: 0.114

Asia WGS AF: 0.202 AC: 701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

PCNT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2023

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). -

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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.24
Dann	Benign	0.41

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: rs9983522; hg19: chr21-47851796; COSMIC: COSV64029370;