rs2839246

chr21-46418209-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.6927A>G(p.Lys2309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 1,570,046 control chromosomes in the GnomAD database, including 11,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4400 hom., cov: 33)
  • Exomes 𝑓: 0.078 (7029 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.524

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=-0.59).
• BP6: Variant 21-46418209-A-G is Benign according to our data. Variant chr21-46418209-A-G is described in ClinVar as [Benign]. Clinvar id is 138628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46418209-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.524 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.6927A>G	p.Lys2309=	synonymous_variant	31/47	ENST00000359568.10
PCNT	NM_001315529.2	c.6573A>G	p.Lys2191=	synonymous_variant	31/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.6927A>G	p.Lys2309=	synonymous_variant	31/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26886 AN: 152090 Hom.: 4395 Cov.: 33

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0918

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.0940 AC: 23543 AN: 250346 Hom.: 2147 AF XY: 0.0889 AC XY: 12035 AN XY: 135414

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0851

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.0868

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0807

GnomAD4 exome AF: 0.0784 AC: 111215 AN: 1417838 Hom.: 7029 Cov.: 27 AF XY: 0.0780 AC XY: 55273 AN XY: 708320

Gnomad4 AFR exome AF: 0.446

Gnomad4 AMR exome AF: 0.0592

Gnomad4 ASJ exome AF: 0.0830

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.0834

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.0686

Gnomad4 OTH exome AF: 0.0947

GnomAD4 genome AF: 0.177 AC: 26924 AN: 152208 Hom.: 4400 Cov.: 33 AF XY: 0.174 AC XY: 12924 AN XY: 74434

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.0938

Gnomad4 ASJ AF: 0.0864

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.0916

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.0762

Gnomad4 OTH AF: 0.166

Alfa AF: 0.0879 Hom.: 1375

Bravo AF: 0.187

Asia WGS AF: 0.104 AC: 362 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0692

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	-0.59
Cadd	Benign	3.3
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2839246; hg19: chr21-47838123;