rs61735824

chr21-46334627-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.498A>G(p.Pro166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,598,466 control chromosomes in the GnomAD database, including 1,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (120 hom., cov: 34)
  • Exomes 𝑓: 0.037 (1405 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.46

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=-0.98).
• BP6: Variant 21-46334627-A-G is Benign according to our data. Variant chr21-46334627-A-G is described in ClinVar as [Benign]. Clinvar id is 138612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46334627-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.498A>G	p.Pro166=	synonymous_variant	3/47	ENST00000359568.10
PCNT	NM_001315529.2	c.144A>G	p.Pro48=	synonymous_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.498A>G	p.Pro166=	synonymous_variant	3/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5283 AN: 151692 Hom.: 122 Cov.: 34

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0481

GnomAD3 exomes AF: 0.0321 AC: 8006 AN: 249372 Hom.: 226 AF XY: 0.0329 AC XY: 4439 AN XY: 134900

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0986

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0156

Gnomad FIN exome AF: 0.00716

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0426

GnomAD4 exome AF: 0.0372 AC: 53750 AN: 1446656 Hom.: 1405 Cov.: 33 AF XY: 0.0372 AC XY: 26769 AN XY: 719826

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.0265

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.00825

Gnomad4 NFE exome AF: 0.0405

Gnomad4 OTH exome AF: 0.0397

GnomAD4 genome AF: 0.0348 AC: 5281 AN: 151810 Hom.: 120 Cov.: 34 AF XY: 0.0325 AC XY: 2412 AN XY: 74264

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.0446

Gnomad4 OTH AF: 0.0466

Alfa AF: 0.0332 Hom.: 59

Bravo AF: 0.0414

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 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	-0.98
Cadd	Benign	1.2
Dann	Benign	0.12

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: rs61735824; hg19: chr21-47754541; COSMIC: COSV64028262;