rs61735822

chr21-46334649-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):c.520A>G(p.Ile174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,568,000 control chromosomes in the GnomAD database, including 1,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (128 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1418 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.64

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017138422).
• BP6: Variant 21-46334649-A-G is Benign according to our data. Variant chr21-46334649-A-G is described in ClinVar as [Benign]. Clinvar id is 138613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46334649-A-G is described in Lovd as [Benign]. Variant chr21-46334649-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.520A>G	p.Ile174Val	missense_variant	3/47	ENST00000359568.10
PCNT	NM_001315529.2	c.166A>G	p.Ile56Val	missense_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.520A>G	p.Ile174Val	missense_variant	3/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5356 AN: 138672 Hom.: 130 Cov.: 33

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0652

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.000407

Gnomad SAS AF: 0.0198

Gnomad FIN AF: 0.00611

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0547

GnomAD3 exomes AF: 0.0322 AC: 8016 AN: 248896 Hom.: 244 AF XY: 0.0330 AC XY: 4443 AN XY: 134656

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0263

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.00704

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0433

GnomAD4 exome AF: 0.0352 AC: 50271 AN: 1429206 Hom.: 1418 Cov.: 33 AF XY: 0.0353 AC XY: 25108 AN XY: 711208

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.0265

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.000281

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.00816

Gnomad4 NFE exome AF: 0.0380

Gnomad4 OTH exome AF: 0.0388

GnomAD4 genome AF: 0.0386 AC: 5354 AN: 138794 Hom.: 128 Cov.: 33 AF XY: 0.0360 AC XY: 2449 AN XY: 68016

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.0394

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.000408

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00611

Gnomad4 NFE AF: 0.0480

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0460 Hom.: 71

TwinsUK AF: 0.0448 AC: 166

ALSPAC AF: 0.0379 AC: 146

ESP6500AA AF: 0.0247 AC: 109

ESP6500EA AF: 0.0557 AC: 479

ExAC AF: 0.0328 AC: 3969

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.0050
Dann	Benign	0.16
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00039	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.010
Sift	Benign	0.24	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.068
ClinPred		0.0043	T
GERP RS		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.023

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: rs61735822; hg19: chr21-47754563; COSMIC: COSV64025491;