rs61735543

Positions:

• chr21-46411608-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.5535G>A​(p.Arg1845Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,006 control chromosomes in the GnomAD database, including 1,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (635 hom., cov: 34)
  • Exomes 𝑓: 0.019 (952 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.90

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 21-46411608-G-A is Benign according to our data. Variant chr21-46411608-G-A is described in ClinVar as [Benign]. Clinvar id is 138620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46411608-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.5535G>A	p.Arg1845Arg	synonymous_variant	28/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.5181G>A	p.Arg1727Arg	synonymous_variant	28/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.5535G>A	p.Arg1845Arg	synonymous_variant	28/47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9227 AN: 152172 Hom.: 631 Cov.: 34

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0823

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0314 AC: 7774 AN: 247432 Hom.: 390 AF XY: 0.0317 AC XY: 4278 AN XY: 134758

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.00289

Gnomad SAS exome AF: 0.0736

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0188 AC: 27402 AN: 1460716 Hom.: 952 Cov.: 34 AF XY: 0.0200 AC XY: 14546 AN XY: 726714

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.00159

Gnomad4 SAS exome AF: 0.0707

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.0283

GnomAD4 genome AF: 0.0607 AC: 9251 AN: 152290 Hom.: 635 Cov.: 34 AF XY: 0.0604 AC XY: 4499 AN XY: 74466

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0304

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.0820

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0671

Alfa AF: 0.0321 Hom.: 140

Bravo AF: 0.0657

Asia WGS AF: 0.0800 AC: 279 AN: 3476

EpiCase AF: 0.0126

EpiControl AF: 0.0134

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	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. -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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). -

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	-0.44
CADD	Benign	4.1
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61735543; hg19: chr21-47831522;