rs34500739

chr21-46346199-T-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.711T>G(p.His237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 1,612,714 control chromosomes in the GnomAD database, including 2,673 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (231 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2442 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.738

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=0.0030015707).
• BP6: Variant 21-46346199-T-G is Benign according to our data. Variant chr21-46346199-T-G is described in ClinVar as [Benign]. Clinvar id is 138615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46346199-T-G is described in Lovd as [Benign]. Variant chr21-46346199-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.711T>G	p.His237Gln	missense_variant	4/47	ENST00000359568.10
PCNT	NM_001315529.2	c.357T>G	p.His119Gln	missense_variant	4/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.711T>G	p.His237Gln	missense_variant	4/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0503 AC: 7631 AN: 151752 Hom.: 232 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0642

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.0846

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0627

Gnomad OTH AF: 0.0482

GnomAD3 exomes AF: 0.0459 AC: 11544 AN: 251320 Hom.: 302 AF XY: 0.0452 AC XY: 6148 AN XY: 135890

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0648

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0861

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0546 AC: 79811 AN: 1460848 Hom.: 2442 Cov.: 33 AF XY: 0.0535 AC XY: 38885 AN XY: 726768

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.0637

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0832

Gnomad4 NFE exome AF: 0.0603

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0503 AC: 7634 AN: 151866 Hom.: 231 Cov.: 32 AF XY: 0.0496 AC XY: 3684 AN XY: 74200

Gnomad4 AFR AF: 0.0380

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.0642

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00893

Gnomad4 FIN AF: 0.0846

Gnomad4 NFE AF: 0.0627

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0553 Hom.: 464

Bravo AF: 0.0457

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0581 AC: 224

ESP6500AA AF: 0.0436 AC: 192

ESP6500EA AF: 0.0614 AC: 528

ExAC AF: 0.0465 AC: 5644

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0548

EpiControl AF: 0.0541

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	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	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 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
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.7
Dann	Benign	0.38
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00020	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.050
MutPred		0.28		Loss of catalytic residue at L236 (P = 0.1265);
MPC		0.081
ClinPred		0.00022	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.038

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: rs34500739; hg19: chr21-47766113; COSMIC: COSV64033626; COSMIC: COSV64033626;