rs61735818

chr21-46428436-G-Achr21-46428436-G-T

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.7536G>A(p.Pro2512=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,612,398 control chromosomes in the GnomAD database, including 2,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (226 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2521 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.59

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=-0.88).
• BP6: Variant 21-46428436-G-A is Benign according to our data. Variant chr21-46428436-G-A is described in ClinVar as [Benign]. Clinvar id is 138603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46428436-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.7536G>A	p.Pro2512=	synonymous_variant	35/47	ENST00000359568.10
PCNT	NM_001315529.2	c.7182G>A	p.Pro2394=	synonymous_variant	35/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.7536G>A	p.Pro2512=	synonymous_variant	35/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7234 AN: 152240 Hom.: 227 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0493

GnomAD3 exomes AF: 0.0459 AC: 11394 AN: 248050 Hom.: 310 AF XY: 0.0455 AC XY: 6136 AN XY: 134900

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0718

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0552 AC: 80630 AN: 1460040 Hom.: 2521 Cov.: 33 AF XY: 0.0542 AC XY: 39372 AN XY: 726302

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.0711

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0835

Gnomad4 NFE exome AF: 0.0613

Gnomad4 OTH exome AF: 0.0513

GnomAD4 genome AF: 0.0475 AC: 7232 AN: 152358 Hom.: 226 Cov.: 33 AF XY: 0.0470 AC XY: 3502 AN XY: 74500

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.0638

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0498 Hom.: 116

Bravo AF: 0.0429

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0558

EpiControl AF: 0.0555

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	Mar 31, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.058
Dann	Benign	0.41
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61735818; hg19: chr21-47848350; COSMIC: COSV64033659; COSMIC: COSV64033659;